2-Pyridone derivatives as inhibitors of neutrophile elastase

ABSTRACT

There are provided novel compounds of formula (I) wherein R 1?, R 4?. R 5?, G 1?, G 2?, X, L, Y 1?, Y 2? and n are as defined in the Specification and optical isomers, racemates and tautomers thereof, and pharmaceutically acceptable salts thereof; together with processes for their preparation, compositions containing them and their use in therapy. The compounds are inhibitors or neutrophil elastase.

FIELD OF THE INVENTION

This invention relates to novel 2-pyridone derivatives, processes fortheir preparation, pharmaceutical compositions comprising them, andtheir use in therapy.

BACKGROUND OF THE INVENTION

Elastases are possibly the most destructive enzymes in the body, havingthe ability to degrade virtually all connective tissue components. Theuncontrolled proteolytic degradation by elastases has been implicated ina number of pathological conditions. Human neutrophil elastase (hNE), amember of the chymotrypsin superfamily of serine proteases is a 33-KDaenzyme stored in the azurophilic granules of the neutrophils. Inneutrophils the concentration of ME exceeded 5 mM and its total cellularamount has been estimated to be up to 3 pg. Upon activation, NE israpidly released from the granules into the extracellular space withsome portion remaining bound to neutrophil plasma membrane (See Kawabatet al. 2002, Eur. J. Pharmacol. 451, 1-10). The main intracellularphysiological function of NE is degradation of foreign organic moleculesphagocytosed by neutrophils, whereas the main target for extracellularelastase is elastin (Janoff and Scherer, 1968, J. Exp. Med. 128,1137-1155). NE is unique, as compared to other proteases (for example,proteinase 3) in that it has the ability to degrade almost allextracellular matrix and key plasma proteins (See Kawabat et al., 2002,Eur. J. Pharmacol. 451, 1-10). It degrades a wide range of extracellularmatrix proteins such as elastin, Type 3 and type 4 collagens laminin,fibronectin, cytokines etc. (Ohbayashi, E, 2002, Expert Opin. Investig.Drugs, 11, 965-980). NE is a major common mediator of many pathologicalchanges seen in chronic lung disease including epithelial damage(Stockley, R. A. 1994, Am. J. Resp. Crit. Care Med 150, 109-113).

The destructive role of NE was solidified almost 40 years ago whenLaurell and Eriksson reported an association of chronic airflowobstruction and emphysema with deficiency of serum α₁-antitrypsin(Laurell and Eriksson, 1963, Scand. J. Clin. Invest. 15, 132-140).Subsequently it was determined that α₁-antitrypsin is the most importantendogenous inhibitor of human NB. The imbalance between human NE andendogenous antiprotease is believed to cause excess human NB inpulmonary tissues which is considered as a major pathogenic factor inchronic obstructive pulmonary disease (COPD). The excessive human NEshows a prominent destructive profile and actively takes part indestroying the normal pulmonary structures, followed by the irreversibleenlargement of the respiratory airspaces, as seen mainly in emphysema.There is an increase in neutrophil recruitment into the lungs which isassociated with increased lung elastase burden and emphysema inα₁-proteinase inhibitor-deficient mice (Cavarra et al., 1996, Lab.Invest. 75, 273-280). Individuals with higher levels of the NEa,protease inhibitor complex in bronchoalveolar lavage fluid showsignificantly accelerated decline in lung functions compared to thosewith lower levels (Betsuyaku et al. 2000, Respiration, 67, 261-267).Instillation of human NE via the trachea in rats causes lunghaemorrhage, neutrophil accumulation during acute phase andemphysematous changes during chronic phase (Karaki et al., 2002, Am. J.Resp. Crit. Care Med., 166,496-500). Studies have shown that the acutephase of pulmonary emphysema and pulmonary haemorrhage caused by NE inhamsters can be inhibited by pre-treatment with inhibitors of NE (Fujieet al., 1999, Inflamm. Res. 48, 160-167).

Neutrophil-predominant airway inflammation and mucus obstruction of theairways are major pathologic features of COPD, including cystic fibrosisand chronic bronchitis. NE impairs mucin production, leading to mucusobstruction of the airways. NE is reported to increase the expression ofmajor respiratory mucin gene, MUC5AC (Fischer, B. M & Voynow, 2002, Am.J. Respir. Cell Biol., 26, 447-452). Aerosol administration of NE toguinea pigs produces extensive epithelial damage within 20 minutes ofcontact (Suzuki et al., 1996, Am. J. Resp. Crit. Care Med., 153,1405-1411). Furthermore NE reduces the ciliary beat frequency of humanrespiratory epithelium int vitro (Smallman et al., 1984, Thorax, 39,663-667) which is consistent with the reduced mucociliary clearance thatis seen in COPD patients (Currie et al., 1984, Thorax, 42, 126-130). Theinstillation of NE into the airways leads to mucus gland hyperplasia inhamsters (Lucey et al., 1985, Am. Resp. Crit. Care Med., 132, 362-366).A role for NE is also implicated in mucus hypersecretion in asthma. Inan allergen sensitised guinea pig acute asthma model an inhibitor of NEprevented goblet cell degranulation and mucus hypersecretion (Nadel etal., 1999, Eur. Resp. J., 13, 190-196).

NE has been also shown to play a role in the pathogenesis of pulmonaryfibrosis. NE: α₁-protenase inhibitor complex is increased in serum ofpatients with pulmonary fibrosis, which correlates with the clinicalparameters in these patients (Yamanouchi et al., 1998, Eur. Resp. J. 11,120-125). In a murine model of human pulmonary fibrosis, a NE inhibitorreduced bleomycin-induced pulmonary fibrosis (Taooka et al., 1997, Am.J. Resp. Crit. Care Med., 156, 260-265). Furthermore investigators haveshown that NE deficient mice are resistant to bleomycin-inducedpulmonary fibrosis (Dunsmore et al., 2001, Chest, 120, 35S-36S). PlasmaNE level was found to be elevated in patients who progressed to ARDSimplicating the importance of NE in early ARDS disease pathogenesis.(Donnelly et al., 1995, Am. J. Res. Crit. Care Med., 151, 428-1433). Theantiproteases and NE complexed with antiprotease are increased in lungcancer area (Marchandise et al., 1989, Eur. Resp. J. 2, 623-629). Recentstudies have shown that polymorphism in the promoter region of the NEgene are associated with lung cancer development (Taniguchi et al.,2002, Clin. Cancer Res., 8, 1115-1120.

Acute lung injury caused by endotoxin in experimental animals isassociated with elevated levels of NE (Kawabata, et al., 1999, Am. J.Resp. Crit. Care, 161, 2013-2018). Acute lung inflammation caused byintratracheal injection of lipopolysaccharide in mice has been shown toelevate the NE activity in bronchoalveolar lavage fluid which issignificantly inhibited by a NE inhibitor (Fujie et al., 1999, Eur. J.Pharmacol., 374, 117-125; Yasui, et al., 1995, Bur. Resp. J., 8,1293-1299). NE also plays an important role in the neutrophil-inducedincrease of pulmonary microvascular permeability observed in a model ofacute lung injury caused by tumor necrosis factor α (TNFα) and pborbolmyristate acetate (PMA) in isolated perfused rabbit lungs (Miyazaki etal., 1998, Am. J. Respir. Crit. Care Med., 157, 89-94).

A role for NE has also been suggested in monocrotoline-induced pulmonaryvascular wall thickening and cardiac hypertrophy (Molteni et al., 1989,Biochemical Pharmacol. 38, 2411-2419). Serine elastase inhibitorreverses the monocrotaline-induced pulmonary hypertension andremodelling in rat pulmonary arteries (Cowan et al., 2000, NatureMedicine, 6, 698-702). Recent studies have shown that serine elastase,that is, NE or vascular elastase are important in cigarettesmoke-induced muscularisation of small pulmonary arteries in guinea pigs(Wright et al., 2002, Am. J. Respir. CriL Care Med., 166, 954-960).

NE plays a key role in experimental cerebral ischemic damage (Shimakuraet al., 2000, Brain Research, 858, 55-60), ischemia-reperfusion lunginjury (Kishima et al., 1998, Ann. Thorac. Surg. 65, 913-918) andmyocardial ischemia in rat heart (Tiefenbacher et al., 1997, Eur. 3.Physiol., 433, 563-570). Human NE levels in plasma are significantlyincreased above normal in inflammatory bowel diseases, for example,Crohn's disease and ulcerative colitis (Adeyemi et al., 1985, Gut, 26,1306-1311). In addition NE has also been assumed to be involved in thepathogenesis of rheumatoid arthritis (Adeyemi et al., 1986, Rheumatol.Int., 6, 57). The development of collegen induced arthritis in mice issuppressed by a NE inhibitor (Kakimoto et al., 1995, Cellular Immunol.165, 26-32).

Thus, human NE is known as one of the most destructive serine proteasesand has been implicated in a variety of inflammatory diseases. Theimportant endogenous inhibitor of human NE is α₁-antitrypsin. Theimbalance between human NE and antiprotease is believed to give rise toan excess of human NE, resulting in uncontrolled tissue destruction. Theprotease/antiprotease balance may be upset by a decreased availabilityof α₁-antitrypsin either through inactivation by oxidants such ascigarette smoke, or as a result of genetic inability to producesufficient serum levels. Human NE has been implicated in the promotionor exacerbation of a number of diseases such as pulmonary emphysema,pulmonary fibrosis, adult respiratory distress syndrome (ARDS), ischemiareperfusion injury, rheumatoid arthritis and pulmonary hypertension.

WO 02/053543 discloses pyridone derivatives having affinity forcannabinoid 2-type receptor.

The present invention discloses novel 2-pyridone derivatives that areinhibitors of human neutrophil elastase and homologous serine proteasessuch as proteinase 3 and pancreatic elastase, and are thereby useful intherapy.

DISCLOSURE OF THE INVENTION

The present invention provides a compound of formula (I)

wherein

-   X represents O or S;-   Y¹ represents N or CR²; and when R¹ represents OH, Y¹ may also, in    the tautomeric form, represent NR⁶;-   Y² represents CR³; and when Y¹ represents CR², then Y² may also    represent N;-   R¹represents H or C1 to 6 alkyl; said alkyl being optionally    substituted by one or more substituents selected independently from    halogen, CN, CHO, OR⁷, NR⁸R⁹, S(O)_(m)R¹⁰ and SO₂NR¹¹R¹²;-   and, when Y represents N. R¹ may also represent OH;-   R⁷ represents H, C1 to 6 alkyl or phenyl; said phenyl being    optionally further substituted by halogen, C1 to 6 alkyl and C1 to 6    alkoxy;-   R⁷ represents H halogen or C1 to 6 alkyl;-   R³ represents H or F;-   G¹ represents phenyl or a five- or six-membered heteroaromatic ring    containing 1 to 3 heteroatoms independently selected from O, S and    N; or G represents a five- or six-membered saturated or partially    unsaturated cycloalkyl ring; or G represents a five- or six-membered    saturated or partially unsaturated heterocyclic ring containing one    heteroatom selected from O, S and NR¹³ where R¹³ represents H or C1    to 6 alkyl;-   R⁵ represents H, halogen, C1 to 6 alkyl, CN, C1 to 6 alkoxy, NO₂,    NR¹⁴R¹⁵, C1 to 3 alkyl substituted by one or more F atoms or C1 to 3    alkoxy substituted by one or more F atoms;-   R¹⁴ and R¹⁵ independently represent H or C1 to 3 alkyl; said alkyl    being optionally further substituted by one or more F atoms;-   n represents an integer 1, 2 or 3 and when n represents 2 or 3, each    R⁵ group is selected independently;-   R⁴ and R⁶ independently represent H or C1 to 6 alkyl; said alkyl    being optionally further substituted by OH or C1 to 6 alkoxy;-   or R⁴ and L are joined together such that the group —NR⁴L represents    a 5 to 7 membered azacyclic ring optionally incorporating one    further heteroatom selected from O, S and NR¹⁶;-   L represents a bond, O, NR²⁹ or C1 to 6 alkyl; said alkyl optionally    incorporating a heteroatom selected from O, S and NR¹⁶; and said    alkyl being optionally further substituted by OH or OMe;-   G² represents a monocyclic ring system selected from:-   i) phenyl or phenoxy,-   ii) a 5 or 6 membered heteroaromatic ring containing one to three    heteroatoms independently selected from O, S and N.-   iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or-   iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring    containing one or two heteroatoms independently selected from O,    S(O)_(p) and NR¹⁷ and optionally further incorporating a carbonyl    group; or-   G² represents a bicyclic ring system in which each of the two rings    is independently selected from:-   i) phenyl,-   ii) a 5 or 6 membered heteroaromatic ring containing one to three    heteroatoms independently selected from O, S and N.-   iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or-   iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring    containing one or two heteroatoms independently selected from O,    S(O)_(p) and NR¹⁷ and optionally further incorporating a carbonyl    group;-   and the two rings are either fused together, or are bonded directly    together or are separated by a linker group selected from O,    S(O)_(q) or CH₂,-   said monocyclic or bicyclic ring system being optionally further    substituted by one to three substituents independently selected from    CN, OH, C1 to 6 alkyl, C1 to 6 alkoxy, halogen, NR¹⁸R¹⁹, NO₂,    OSO₂R³⁸, CO₂R²⁰, C(═NH)NH₂, C(O)NR²¹R²², C(S)NR²³R²⁴, SC(═NH)NH₂,    NR³¹C(═NH)NH₂, S(O)_(S)R²⁵, SO₂NR²⁶R²⁷, C1 to 3 alkoxy substituted    by one or more P atoms and C1 to 3 alkyl substituted by SO₂R³⁹ or by    one or more P atoms; or-   when L does not represent a bond, G² may also represent H;-   m, p, q, s and t independently represent an integer 0, 1 or 2;-   R⁸ and R⁹ independently represent H, C1 to 6 alkyl, formyl or C2 to    6 alkanoyl; said alkyl being optionally further substituted by    phenyl optionally substituted by halogen, C1 to 6 alkyl, C1 to 6    alkoxy or SO₂R³⁰;-   or the group NR⁸R⁹ together represents a 5 to 7 membered azacyclic    ring optionally incorporating one further heteroatom selected from    O, S and NR²⁸;-   R¹⁸ and R¹⁹ independently represent H, C1 to 6 alkyl, formyl, C2 to    6 alkanoyl, S(O)_(t)R³² or SO₂NR³³R³⁴; said alkyl group being    optionally further substituted by halogen, CN, C1 to 4 alkoxy or    CONR⁴¹R⁴²;-   R²⁵ represents H, C1 to 6 alkyl or C3 to 6 cycloalkyl; said alkyl    group being optionally further substituted by one or more    substituents selected independently from OH, CN, CONR³⁵R³⁶, CO₂R³⁷,    OCOR⁴⁰, C3 to 6 cycloalkyl, a C4 to 7 saturated heterocyclic ring    containing one or two heteroatoms independently selected from O,    S(O)_(p) and NR⁴³ and phenyl or a 5 or 6 membered heteroaromatic    ring containing one to three heteroatoms independently selected from    O, S and N; said aromatic ring being optionally further substituted    by one or more substituents selected independently from halogen, CN,    C1 to 4 alkyl, C1 to 4 alkoxy, OH, CONR⁴⁴R⁴⁵, CO₂R⁴⁶, S(O)_(s)R⁴⁷    and NHCOCH₃;-   R²⁶ and R²⁷ independently represent H, C1 to 6 alkyl, formyl or C2    to 6 alkanoyl;-   R³² represents H, C1 to 6 alkyl or C3 to 6 cycloalkyl;-   R³⁸ represents H, C1 to 6 alkyl or phenyl; said phenyl being    optionally further substituted by halogen, C1 to 6 alkyl or C1 to 6    alkoxy;-   R¹⁰, R¹¹, R¹², R¹⁶, R¹⁷, R²⁰, R²¹, R²², R²³, R²⁴, R²⁸, R²⁹, R³⁰,    R³¹, R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁶ and    R⁴⁷ independently represent H or C1 to 6 alkyl;    and pharmaceutically acceptable salts thereof, with the proviso that    the following compounds are disclaimed:-   N-benzyl-5,6-dimethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide;-   N-(2-phenethyl)-5,6-dimethyl-2-ox-1-phenyl-1,2-dihydropyridine-3-carboxamide;-   N-(2-hydroxyethyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide;-   N-[2-(dimethylamino)ethyl]-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide;-   4-[2-[[[1,2-dihydro-1-(4-methylcyclohexyl)-2-oxo-3-pyridinyl]carbonyl]amino]ethyl]-benzoic    acid; and-   4-[2-[[(1-cyclohexyl-1,2-dihydro-2-oxo-3-pyridinyl]carbonyl]amino]ethyl]-benzoic    acid.

The compounds of formula (I) may exist in enantiomeric forms. It is tobe understood that all enantiomers, diastereomers, racemates andmixtures thereof are included within the scope of the invention.

Compounds of formula (I) may also exist in various tautomeric forms.Thus, for example, compounds of formula (I) wherein R¹ represents OH andY represents N, are tautomers of compounds of formula (Ia) wherein R⁶represents H.

All possible tautomeric forms and mixtures thereof are included withinthe scope of the invention. Compounds of formula (Ia) wherein R⁶represents H or optionally substituted C1 to 6 alkyl are thusspecifically included within the scope of the invention.

Unless otherwise indicated, the term “C1 to 6 alkyl” referred to hereindenotes a straight or branched chain alkyl group having from 1 to 6carbon atoms. Examples of such groups include methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, t-butyl, pentyl and hexyl. The terms “C1 to3 alkyl” and “C1 to 4 alkyl” are to be interpreted analogously.

Examples of “C1 to 3 alkyl substituted by one or more F atoms” includefluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,1,1-difluoroethyl, pentafluoroethyl and 3,3,3-trifluoropropyl.

Unless otherwise indicated, the term “C1 to 6 alkoxy” referred to hereindenotes an oxygen substituent bonded to a straight or branched chainalkyl group having from 1 to 6 carbon atoms. Examples of such groupsinclude methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy ands-butoxy. The terms “C1 to 3 alkoxy” and “C1 to 4 alkoxy” are to beinterpreted analogously.

Examples of “C1 to 3 alkoxy substituted by one or more F atoms” includefluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy and3,3,3-trifluoropropoxy.

Unless otherwise indicated, the term “C2 to 6 alkanoyl” referred toherein denotes a straight or branched chain alkyl group having from 1 to5 carbon atoms bonded to the molecule via a carbonyl group. Examples ofsuch groups include acetyl, propionyl and pivaloyl.

Unless otherwise indicated, the term “halogen” referred to hereindenotes fluorine, chlorine, bromine and iodine.

Examples of a five or six membered heteroaromatic ring containing 1 to 3heteroatoms independently selected from O, S and N include furan,thiophene, pyrrole, oxazole, oxadiazole, isoxazole, imidazole, thiazole,triazole, thiadiazole, pyridine, pyrimidine and pyrazine.

Unless otherwise indicated, the term “C3 to 6 saturated or partiallyunsaturated cycloalkyl” referred to herein denotes a 3 to 6 memberednon-aromatic carbocyclic ring optionally incorporating one or moredouble bonds. Examples include cyclopropyl, cyclopentyl, cyclopentenyl,cyclohexyl and cyclohexenyl. The term “five- or six-membered saturatedor partially unsaturated cycloalkyl ring” is to be interpretedanalogously.

Unless otherwise indicated, the term “C4 to 7 saturated or partiallyunsaturated heterocyclic ring containing one or two heteroatomsindependently selected from O, S(O)_(p) and NR¹⁷ and optionally furtherincorporating a carbonyl group” referred to herein denotesl a 4 to 7membered non-aromatic heterocyclic ring optionally incorporating one ormore double bonds and optionally incorporating a carbonyl group.Examples include tetrahydrofuran, thiolane 1,1-dioxide, tetrahydropyran,4-oxo-4H-pyran, pyrrolidine, pyrroline, imidazolidine, 1,3-dioxolane,piperidine, piperazine, morpholine, perhydroazepine, pyrrolidone andpiperidone. The term “five- or six-membered saturated or partiallyunsaturated heterocyclic ring containing one heteroatom selected from O,S and NR¹³” is to be interpreted analogously.

Examples of a “5 to 7 membered azacyclic ring optionally incorporatingone further heteroatom selected from O, S and NR¹⁶” include pyrrolidine,piperidine, morpholine, thiomorpholine and piperazine.

In the definition of L, “C1 to 6 alkyl; said alkyl optionallyincorporating a heteroatom selected from O, S and NR¹⁶” embraces astraight or branched chain arrangement of 1 to 6 carbon atoms in whichany two carbon atoms are optionally separated by O, S or NR¹⁶ Thedefinition thus includes, for example, methylene, ethylene, propylene,hexamethylene, ethylethylene, —CH₂CH₂O—CH₂—, —CH₂CH₂O—CH₂—CH₂—,—CH₂CH₂S— and —CH₂CH₂NR¹⁶—.

Examples of bicyclic ring systems in which the two rings are eitherfused together, or are bonded directly together or are separated by alinker group selected from O, S(O)_(q) or CH₂ include biphenyl,thienylphenyl, pyrazolylphenyl, phenoxyphenyl, naphthyl, indanyl,quinolyl, tetrahydroquinolyl, benzofuranyl, indolyl, isoindolyl,indolinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl,benzthiazolyl, purinyl, isoquinolyl, chrormanyl, indenyl, quinazolyl,quinoxalyl, chromanyl, isocromanyl, 3H-indolyl, 1H-indazolyl,quinuclidyl, tetrahydronaphthyl, dihydrobenzofuranyl,morpholine-4-ylphenyl, 1,3-benzodioxolyl,1,1-dioxido-2,3-dihydro-1-benzothienyl, 2,3-dihydro-1,4-benzodioxinyland 3,4-dihydro-isochromenyl.

Examples of bicyclic ring systems in which the two rings are separatedby a linker group S(O)_(q) include 4-(piperazin-1-ylsulfonyl)phenyl,4-(morpholin-4-ylsulfonyl)phenyl, 4-(piperidin-1-ylsulfonyl)phenyl,4-(pyrrolidin-1-ylsulfonyl)phenyl, 4-(4-pyridinylsulfonyl)phenyl,4-(phenylsulfonyl)phenyl, 4-(thiazolylsulfonyl)phenyl,4-(pyrimidin-2-ylsulfonyl)phenyl, 4-(imidazolylsulfonyl)phenyl,4-(triazolylsulfonyl)phenyl and 4-(oxazolylsulfonyl)phenyl.

In one embodiment, R⁵ represents H, halogen, C1 to 6 alkyl, CN, C1 to 6alkoxy, C1 to 3 alkyl substituted by one or more F atoms or C1 to 3alkoxy substituted by one or more F atoms. In another embodiment, R⁵represents halogen, C1 to 6 alkyl, CN, C1 to 6 alkoxy or C1 to 3 alkylsubstituted by one or more F atoms. In another embodiment, R⁵ representshalogen, CH₃, CN, OCH₃ or CF₃.

In one embodiment, n represents an integer 1 or 2. E another embodiment,n represents the integer 1.

In one embodiment, R⁵ represents halogen, CN or CF₃; n represents theinteger 1; and G¹ represents phenyl.

In one aspect, the invention provides compounds of formula (I) wherein Xrepresents O; Y¹ represents CR²; Y² represents CR³; R¹ representsoptionally substituted C1 to 6 alkyl; G¹ represents phenyl or a five- orsix-membered heteroaromatic ring containing 1 to 3 heteroatomsindependently selected from O, S and N; R⁴ represents H; L represents C1to 6 alkyl; and G² represents an optionally substituted monocyclic ringsystem selected from:

-   i) phenyl,-   ii) a 5 or 6 membered heteroaromatic ring containing one to three    heteroatoms independently selected from O, S and N,-   iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or-   iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring    containing one or two heteroatoms independently selected from O,    S(O)_(p) and NR¹⁷ and optionally further incorporating a carbonyl    group.

In another aspect the invention provides compounds of formula (I)wherein X represents O; Y¹ represents CR²; Y² represents CR³; R¹represents C1 to 6 alkyl, R² and R³ each represent H; G¹ representsphenyl or a five- or six-membered heteroaromatic ring containing 1 to 3heteroatoms independently selected from O, S and N; R⁴ represents H; Lrepresents C1 to 6 alkyl; and G² represents an optionally substitutedmonocyclic ring system selected from:

-   i) phenyl,-   ii) a 5 or 6 membered heteroaromatic ring containing one to three    heteroatoms independently selected from O, S and N,-   iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or-   iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring    containing one or two heteroatoms independently selected from O,    S(O)_(p) and NR¹⁷ and optionally further incorporating a carbonyl    group.

In another aspect the invention provides compounds of formula (I)wherein X represents O; Y¹ represents N or NR⁶ and R¹ represents OH or atautomer thereof; Y represents CR³; G¹ represents phenyl or a five- orsix-membered heteroaromatic ring containing 1 to 3 heteroatomsindependently selected from O, S and N; R⁴ represents H; L represents C1to 6 alkyl; and G² represents an optionally substituted monocyclic ringsystem selected from:

-   i) phenyl,-   ii) a 5 or 6 membered heteroaromatic ring containing one to three    heteroatoms independently selected from O, S and N,-   iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or-   iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring    containing one or two heteroatoms independently selected from O,    S(O)_(p) and NR¹⁷ and optionally further incorporating a carbonyl    group.

In another aspect the invention provides compounds of formula (I)wherein X represents O; Y¹ represents CR²; Y represents CR³; R¹represents C1 to 6 alkyl; R² and R³ each represent H; G¹ representsphenyl or pyridyl; R⁴ represents H; L represents C1 to 6 alkyl; and G²represents optionally substituted phenyl.

In another aspect the invention provides compounds of formula (I)wherein X represents O; Y¹ represents CR²; Y² represents CR³; R¹represents C1 to 6 alkyl; R² and R³ each represent H; G¹ representsphenyl or pyridyl; R⁴ represents H; L represents methylene; and G²represents optionally substituted phenyl.

In one embodiment, X in formula (I) represents O.

In one embodiment, the invention discloses compounds of formula (I) inwhich Y¹ represents CR² and Y² represents CR³. In another embodiment,the invention discloses compounds of formula (I) in which Y¹ representsCR² and Y² represents CR³ and R² and R³ each represent H.

In another embodiment, Y¹ represents N. In another embodiment, R¹represents OH in the tautomeric form and Y¹ represents NR⁶.

In one embodiment, R¹ represents optionally substituted C1 to 6 alkyl.In another embodiment, R¹ represents C1 to 6 alkyl, particularly methyl.

In one embodiment, G¹ represents phenyl or a five- or six-memberedheteroaromatic zing containing 1 to 3 heteroatoms independently selectedfrom O, S and N. In another embodiment, G¹ in formula (I) representsphenyl or pyridyl. In another embodiment, G¹ in formula (I) representsphenyl. In another embodiment, G¹ in formula (I) represents phenyl and(R⁵)_(n) represents a CF₃ group in the 3-position.

In one embodiment, R⁴ represents H.

In one embodiment, L represents C1 to 6 alkyl. In another embodiment, Lrepresents —CH₂—. In another embodiment, L represents NR²⁹ and R²⁹represents H.

In one embodiment, G² represents an optionally substituted monocyclicring system selected from:

-   i) phenyl,-   ii) a 5 or 6 membered heteroaromatic ring containing one to three    heteroatoms independently selected from O, S and N,-   iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or-   iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring    containing one or two heteroatoms independently selected from O,    S(O)_(p) and NR¹⁷ and optionally further incorporating a carbonyl    group.

In another embodiment, G² represents optionally substituted phenyl. Inanother embodiment, G² represents phenyl substituted by OSO₂R³⁸,S(O)_(s)R²⁵, SO₂NR²⁶R²⁷, NR¹⁸R¹⁹ (wherein at least one of R¹⁸ and R¹⁹represents S(O)_(t)R³² or SO₂NR³³R³⁴) or C1 to 3 alkyl substituted bySR³⁹.

In another aspect, the invention specifically provides one or morecompounds as described in the Examples herein, or the non-salt formthereof or a pharmaceutically acceptable salt thereof.

Particular compounds include:

-   N-(4-chlorobenzyl)-1-(4-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-(morpholin-4-ylbenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-[4-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[4-(dimethylamino)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[4-(aminosulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(4-methoxybenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-benzyl-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(4-chlorobenzyl)-1-(2-fluoro-5-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(3-chlorobenzyl)-1-(2-fluoro-5-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(2-fluoro-5-methylphenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(4-methoxybenzyl)-1-(3-methoxyphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(3-chlorobenzyl)-1-(3-methoxyphenyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(4-chlorobenzyl-1)-(3-methoxyphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-[4-(aminosulfonyl)benzyl]-1-(3-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(4-chlorobenzyl-1)-(3-chloro-4-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-chloro-4-methylphenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(4-chlorobenzyl)-1-(2,3-dimethylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(4-chlorobenzyl)-1-(3-chloro-4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-chloro-4-fluorophenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(4-chlorobenzyl)-1-(3-ethylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide.-   1-(3-bromophenyl)-N-(4-chlorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-bromophenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-1,    2-dihydropyridine-3-carboxamide-   N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-[3-(2-oxopyrrolidin-1-yl)propyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(4-bromobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(4-chlorophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(4-methoxybenzyl)-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide-   N-(4-chlorobenzyl)-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide-   N-(4-chlorobenzyl)-1-(3,5-dimethylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-[4-(aminosulfonyl)benzyl]-1-(3,5-dimethylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3,5-dimethylphenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-benzyl-1-(3,5-dimethylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(4-chlorobenzyl)-6-methyl-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3    carboxamide-   N-(4-methoxybenzyl)-6-methyl-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(3-chlorobenzyl)-6-methyl-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(4-chlorobenzyl)-1-(3-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(3-chlorobenzyl)-1-(3-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-chlorophenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   methyl    4-[({[1-(3-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl]carbonyl}amino)methyl]benzoate-   4-[({[1-(3-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl]carbonyl}amino)methyl]benzoic    acid-   1-(3-cyanophenyl)-N-(cyclohexylmethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-(2-furylmethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-6-methyl-2-oxo-N-(pyridin-3-ylmethyl)-1,2-dihydropyridine-3-carboxamide-   N-benzyl-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-2,3-dihydro-1H-inden-1-yl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-2-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-6-methyl-2-oxo-N-(3,4,5-trimethoxybenzyl)-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-(2,5-dimethoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-(3,4-dimethoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-[(1-ethylpyrrolidin-2-yl)methyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(4-chlorobenzyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(3-chlorobenzyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-6-methyl-2-oxo-N-(thien-2-ylmethyl)-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-(cyclopropylmethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-(3-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-6-methyl-2-oxo-N-(pyridin-4-ylmethyl)-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-6-methyl-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-[2-(3-chlorophenyl)ethyl]-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-6-methyl-2-oxo-N-(2-pyridin-2-ylethyl)-1,2-dihydropyridine-3-carboxamide-   N-[2-(4-chlorophenyl)ethyl]-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-[2-(2-methoxyphenyl)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-[2-(2-chlorophenyl)ethyl]-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-[2-(3-methoxyphenyl)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-[2-(4-fluorophenyl)ethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-(2-(2,4-dichlorophenyl)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine    3-carboxamide-   1-(3-cyanophenyl)-N-[2-(3-fluorophenyl)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-[2-(2-fluorophenyl)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-(2-cyclohex-1-en-1-ylethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-[2-(4-bromophenyl)ethyl]-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(3-bromobenzyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(4-bromobenzyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(2-bromobenzyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-(3,4-dihydro-2H-pyran-2-ylmethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-6-methyl-N-(4-methylbenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-6-methyl-N-(1-naphthylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-(2-ethoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-6-methyl-N-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-(4-fluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(1,3-benzodioxol-5-ylmethyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-2,4-dichlorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl-6-methyl-N-(2-methylbenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-(3,4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-(3,4-dichlorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-6-methyl-N-[(5-methyl-2-furyl)methyl]-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-6-methyl-2-oxo-N-1,2,3,4-tetrahydronaphthalen-1-yl-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-(2,3-dimethoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-(3,5-dimethoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-[1-(4-fluorophenyl)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-[1-(4-chlorophenyl)ethyl]-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-(2,5-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-(2,3-dihydro-1-benzofuran-5-yl-methyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   methyl    4-[({[1-(3-cyanophenyl)-6-methyl-1,2-oxo-1,2-dihydropyridin-3-yl]carbonyl}amino)methyl]benzoate-   1-(3-cyanophenyl)-6-methyl-2-oxo-N-(4-phenoxybenzyl)-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-6-methyl-2-oxo-N-(thien-3-ylmethyl)-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-6-methyl-N-[(5-methylisoxazol-3-yl)methyl]-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl-1N-[(2,5-dimethyl-3-furyl)methyl]-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-(3-furylmethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-6-methyl-2-oxo-N-[4-(1H-pyrazol-1-yl)benzyl]-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-6-methyl-2-oxo-N-(4-thien-2-ylbenzyl)-1,2-dihydropyridine-3    carboxamide-   N-[4-(aminosulfonyl)benzyl]-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-[2-(1,3-benzodioxol-5-yl)ethyl]-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-6-methyl-2-oxo-N-(2-thien-2-ylethyl)-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-N-[2-(2,4-dimethylphenyl)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-6-methyl-N-[2-(4-methylphenyl)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-{2-[4-(aminosulfonyl)phenyl]ethyl}-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(3-cyanophenyl)-6-methyl-2-oxo-N-[(1S)-1-phenylethyl]-1,2-dihydropyridine-3-carboxamide-   N-(cyclohexylmethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(2-furylmethyl)-6-methyl-2-oxo    1-3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-(pyridin-3-ylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-2,3-dihydro-1H-inden-1-yl-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(2-methoxybenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-(tetrahydrofuran-2-ylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-N-(3,4,5-trimethoxybenzyl)-1,2-dihydropyridine-3-carboxamide-   N-(3-fluorobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(2,5-dimethoxybenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[(1-ethylpyrrolidin-2-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(2-chlorobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(4-chlorobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(3-chlorobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-(thien-2-ylmethyl)-1-[3-trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(cyclopropylmethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(3-methoxybenzyl)-6-methyl-oxo-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-(pyridin-4-ylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[2-(3,4-dimethoxyphenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[2-(4-methoxyphenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-(2-phenylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(2-(3-chlorophenyl)ethyl]J-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-(2-pyridin-2-ylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[2-(2-methoxyphenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[2-(2-chlorophenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[2-(3-methoxyphenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[2-(4-fluorophenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[2-(2,4-dichlorophenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[2-(3-fluorophenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[2-(2-fluorophenyl)ethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(2-cyclohex-1-en-1-ylethyl)-6-methyl-2-oxo-1-[3-(trifluoromethylphenyl]-1,2-dihydropyridine-3-carboxamide-   N-2-(4-bromophenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-[(1S)-1-phenylethyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(3-bromobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(4-bromobenzyl)-6-methyl-2-oxo-1-[3-trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(2-bromobenzyl)-6-methyl-2-oxo-1-[3-trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(3,4-dihydro-2H-pyran-2-ylmethyl)-6-methyl-2-oxo-1-[3-trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-4-methylbenzyl)-2-oxo-1-[3-trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-(1-naphthylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(2-ethoxybenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-(3-methylbenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(4-fluorobenzyl)-6-methyl-2-oxo-1-[3-trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(1,3-benzodioxol-5-ylmethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(2,4-dichlorobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-(2-methylbenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(3,4-difluorobenzyl)-6-methyl-2-oxo    1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(2-fluorobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(2-chloro-4-fluorobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide-   N-(3,4-dichlorobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-[(5-methyl-2-furyl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-1,2,3,4-tetrahydronaphthalen-1-yl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(2,3-dimethoxybenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[1-(4-chlorophenyl)ethyl]-6-methyl-2-oxo-1-(3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(2,5-difluorobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   methyl    4{[({6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-yl}carbonyl)amino]methyl}benzoate-   6-methyl-2-oxo-N-(4-phenoxybenzyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-[(5-methylisoxazol-3-yl)methyl]-2-oxo-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[(2,5-dimethyl-3-furyl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(3-furylmethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-[4-(1H-pyrazol-1-yl)benzyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-(4-thien-2-ylbenzyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[2-(1,3-benzodioxol-5-yl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-(2-thien-2-ylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[2-(4-tert-butylphenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-[2-(4-methylphenyl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,    2-dihydropyridine-3-carboxamide-   N-{2-[4-(aminosulfonyl)phenyl]ethyl})-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-[(1R)-1-phenylethyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   3-{[4-(2-methoxyphenyl)piperazin-1-yl]carbonyl}-6-methyl-1-[3-(trifluoromethyl)phenyl]pyridin-2    (1H)-one-   N-[(4-cyanocyclohexyl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   3-{([4(4-fluorophenyl)piperazin-1-yl]carbonyl}-6-methyl-1-[3-(trifluoromethyl)phenyl]pyridin-2    (1H)-one-   N-[2-(4′-fluoro-1,1′-biphenyl-4-yl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(2-hydroxy-1-phenylethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-[(2R)-2-phenylcyclopropyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[1-(4-chlorobenzyl)piperidin-4-yl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-(2-morpholin-4-ylethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[2-(4-chlorophenyl)ethyl]6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(2-hydroxy-2-phenylethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-cyclopentyl-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[2-(1H-imidazol-4-yl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl-1-phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(3,5-dimethoxybenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(4-hydroxycyclohexyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-(2-pyridin-2-ylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-1H-1,2,4-triazol-3-yl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[1-(hydroxymethyl)-2-methylpropyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   3-{([3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]carbonyl}-methyl-1-[3-(trifluoromethyl)phenyl]pyridin-2    (1H)-one-   6-methyl-2-oxo-N-(pyridin-3-ylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(2-methoxyethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(2-hydroxypropyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   ethyl    4-[({6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl)-1,2-dihydropyridin-3-yl}carbonyl)amino]piperidine-1-carboxylate-   N-[3-(1H-imidazol-1-yl)propyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(4-chlorobenzyl)-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(4-chlorobenzyl)-6′-methyl-2-oxo-2H-1,2′-bipyridine-3-carboxamide-   N-(4-methoxybenzyl)-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide    methyl    4-[({[1-(3-methylphenyl)-2-oxo-1,2-dihydropyridin-3-yl]carbonyl}amino)methyl]benzoate-   4-[({(1-(3-methylphenyl)-2-oxo-1,2-dihydropyridin-3-yl]carbonyl}amino)methyl]benzoic    acid-   N-[4-chlorobenzyl)-1-(2-fluoro-5-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(2-fluoro-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-[4-(dimethylamino)benzyl]-1-(2-fluoro-5-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-[4-(aminosulfonyl)benzyl]-1-(2-fluoro-5-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(4-chlorobenzyl)-4′-methyl-2-oxo-2H-1,2′-bipyridine-3-carboxamide-   N-(4-chlorobenzyl)-1-(2,5-dimethylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide-   1-(2,5-dimethylphenyl)-N-4-methoxybenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-[4-(dimethylamino)benzyl]-1-(2,5-dimethylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(4-chlorobenzyl)-1-[2-methyl-5-(trifluoromethyl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-(4-methoxybenzyl)-1-[2-methyl-5-(trifluoromethyl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-[4-(dimethylamino)benzyl]-1-[2-methyl-5-(trifluoromethyl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide-   N-benzyl-5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(2-chlorobenzyl)-5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   5-methyl-2-oxo-N-(2-phenylethyl)-1-[3-trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(4-chlorophenyl)-5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-ethyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[4-(methylsulfonyl)benzyl]-2-oxo-6-propyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-butyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-(methoxymethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-(hydroxymethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[4-(aminosulfonyl)benzyl]-2,4-dioxo-3-[3-trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-[4-(dimethylamino)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(4-chlorobenzyl)-2,4-dioxo-3-[3-trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(4-bromobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(4-methoxybenzyl)-2,5-dioxo-3-[3-(trifluoromethyl)phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(1,3-benzodioxol-5-ylmethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(3-chlorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-(2-methoxyethyl)-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-methyl-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-ethyl-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(4-chlorobenzyl)-112-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(4-chlorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(4-methoxybenzyl)-1-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-carboxamide-   1-(2-methoxyethyl)-2,4-dioxo-N-(pyridinylmethyl)-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-[2-(3,4-dimethoxyphenyl)ethyl]-1-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-(2-methoxyethyl)-N-[2-(3-methoxyphenyl)ethyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-(2-methoxyethyl)-N-(4-methylbenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-(2-methoxyethyl)-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(4-fluorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(1,3-benzodioxol-5-ylmethyl)-1-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(2-chloro-4-fluorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-3-[3-trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(3,4-dichlorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   methyl    4-{[({1-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4    tetrahydropyrimidin-5-yl}carbonyl)amino]methyl}benzoate-   1-(2-methoxyethyl)-N-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-(2-methoxyethyl)-2,4-dioxo-N-[4-(1H-pyrazol-1-yl)benzyl]-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-4-chlorobenzyl)-3-(3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   3-(3-chlorophenyl)-N-(4-methoxybenzyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   3-(3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-N-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   3-(3-chlorophenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   3-(3-chlorophenyl)-N-(2-methoxyethyl)-N-[2-(3-methoxyphenyl)ethyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(3-bromobenzyl)-3-(3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   3-(3-chlorophenyl)-1-(2-methoxyethyl)-N-(4-methylbenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   3-(3-chlorophenyl)-1-(2-methoxyethyl)-N-(4-(methylsulfonyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   3-(3-chlorophenyl)-N-(4-fluorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(1,3-benzodioxol-5-ylmethyl)-3-(3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   3-(3-chlorophenyl)-N-(3,4-difluorobenzyl)-(2-methoxyethyl)-2,4-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(2-chloro-4-fluorobenzyl)-3-(3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   3-(3-chlorophenyl)-N-(3,4-dichlorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   methyl    4[{([3-(3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-S-yl]carbonyl}amino)methyl]benzoate-   3-(3-chlorophenyl)-1-(2-methoxyethyl)-N-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   3-(3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-N-[4-(1H-pyrazol-1-yl)benzyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-(4-chlorobenzyl)-3-(3-methoxyphenyl)-2,    oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-methoxyphenyl)-N-[2-(3-methoxyphenyl)ethyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(3-bromobenzyl)-1-butyl-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-(4-fluorobenzyl)-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine    5-carboxamide-   N-(1,3-benzodioxol-5-ylmethyl)-1-butyl-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-(2,4-dichlorobenzyl)-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-(3,4-difluorobenzyl)-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-(2-chloro-4-fluorobenzyl)-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-(4-chlorobenzyl)-3-(3-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-chlorophenyl)-N-(4-methoxybenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-chlorophenyl)-2,4-dioxo-N-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-chlorophenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-chlorophenyl)-N-[2-(3-methoxyphenyl)ethyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(3-bromobenzyl)-1-butyl-3-(3-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(4-bromobenzyl)-1-butyl-3-(3-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-chlorophenyl)-N-(4-methylbenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-chlorophenyl)-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-chlorophenyl)-N-(4-fluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(1,3-benzodioxol-5-ylmethyl)-1-butyl-3-(3-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-chlorophenyl)-N-(2,4-dichlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-chlorophenyl)-N-(3,4-difluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-(2-chloro-4-fluorobenzyl)-3-(3-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-chlorophenyl)-N-(3,4-dichlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-chlorophenyl)-N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-chlorophenyl)-N-[(4-cyanocyclohexyl)methyl-3-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-chlorophenyl)-N-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-chlorophenyl)-2,4-dioxo-N-[4-(1H-pyrazol-1-yl)benzyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-chlorophenyl)-2,4-dioxo-N-(3-(2-oxopyrrolidin-1-yl)propyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-(4-chlorobenzyl)-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-cyanophenyl)-N-(4-methoxybenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-cyanophenyl)-2,4-dioxo-N-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-cyanophenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-cyanophenyl)-N-[2-(3-methoxyphenyl)ethyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(3-bromobenzyl)-1-butyl-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(4-bromobenzyl)-1-butyl-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-cyanophenyl)-N-(4-methylbenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-cyanophenyl)-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-cyanophenyl)-N-(4-fluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(1,3-benzodioxol-5-ylmethyl)-1-butyl-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-cyanophenyl)-N-(2,4-dichlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-cyanophenyl)-N-(3,4-difluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-(2-chloro-4-fluorobenzyl)-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-cyanophenyl)-N-(3,4-dichlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-[(4-cyanocyclohexyl)methyl]-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-cyanophenyl)-N-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-cyanophenyl)-2,4-dioxo-N-[4-(1H-pyrazol-1-yl)benzyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-3-(3-cyanophenyl)-2,4-dioxo-N-[3-(2-oxopyrrolidin-1-yl)propyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-(4-chlorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-(4-methoxybenzyl)-2,4-oxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-2,4-dioxo-N-(pyridin-4-ylmethyl)-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-[(3,4-dimethoxyphenyl)ethyl]-2,4-oxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-[2-(3-methoxyphenyl)ethyl]-2,2-oxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(3-bromobenzyl)-1-butyl-2,4-dioxo-3-[3-trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(4-bromobenzyl)-1-butyl-2,4-dioxo-3-[3-trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-(4-methylbenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-(4-fluorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   N-(1,3-benzodioxol-5-ylmethyl)-1-butyl-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-(2,4-dichlorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-(3,4-difluorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-(2-chloro-4-fluorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-(3,4-dichlorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-(2,3-dihydro-1    benzofuran-5-ylmethyl)-2,4-dioxo-3-3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-[(4-cyanocyclohexyl)methyl]-2,4-dioxo-3-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-N-[(5-methylisoxazol-3-yl)methyl]-2,44-oxo-3-[3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-2,4-dioxo-N-[4-(1H-pyrazol-1-yl)benzyl]-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   1-butyl-2,4-dioxo-N-[3-(2-oxopyrrolidin-1-yl)propyl]-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide-   6-(chloromethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[4-(methylsulfonyl)benzyl]-6-[(methylthio)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[4-(methylsulfonyl)benzyl]6-({[4-(methylsulfonyl)benzyl]amino}methyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[4-(methylsulfonyl)benzyl]-6-(morpholin-4-ylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-(cyanomethyl)-N-[4-(methylsulfonyl)benzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-isopropyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[4-(ethylsulfonyl)benzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[3-chloro-4-(methylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-cyclopropanesulfonyl-benzylamide-   N-[3-methoxy-4-(methylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[3-bromo-4-(methylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[3-cyano-4(methylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-[3-methyl-4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-[4-(methylthio)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-[4-(methylsulfinyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(4-(benzylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-[4-(propylsulfonyl)benzyl]-1-(3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[4-(butylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[4-(isobutylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[4-(sec-butylsulfonyl)benzyl]-6-methyl-2-oxo-1-p-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide-   N-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-{4-[(3-methylbutyl)sulfonyl]benzyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-{4-[(cyclopropylmethyl)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-{4-[(tetrahydrofuran-2-ylmethyl)sulfonyl]-benzyl}-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-{4[(2-hydroxyethyl)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-{4-[(cyanomethyl)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-{4[(2-amino-2-oxoethyl)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-{4-[(4-cyanobenzyl)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-{4-[(2-cyanoethyl)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-{4-[(3-hydroxypropyl)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(4-{(2-(dimethylamino)-2-oxoethyl]sulfonyl}benzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   ethyl    3-[(4-{[({6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-yl}3    carbonyl)amino]methyl}phenyl)sulfonyl]propanoate-   2-[(4-{[({6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-yl}carbonyl)amino]methyl}phenyl)sulfonyl]ethyl    acetate-   N-{4-[(3-cyanobenzyl)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   methyl    3-[(4-{[({6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-yl}carbonyl)amino]methyl}phenyl)sulfonyl]propanoate-   6-methyl-N-(4-{[(2-methyl-1,3-thiazol-4-yl)methyl]sulfonyl}benzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-{4-[(pyridin-4-ylmethyl)sulfonyl]benzyl}-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-{4-[(3-cyanopropyl)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(4-{[(3,5-dimethylisoxazol-4-yl)methyl]sulfonyl}benzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(4-{[4-(acetylamino)benzyl]sulfonyl}benzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-[4-({2-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]-2-oxoethyl}sulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-[4-(methylsulfonyl)phenoxy]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydropyridine-3-carboxylic    acid (4 bromo-phenoxy)-amide-   6-methyl-2-oxo-N-phenoxy-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(4-aminobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroproline-3-carboxamide-   6-methyl-N-{4-[(methylsulfonyl)amino]benzyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-{4-[bis(methylsulfonyl)amino]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[[4-[[(dimethylamino)sulfonyl]amino]phenyl]methyl]-1,2-dihydro-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide-   6-methyl-N-{4-[methyl(methylsulfonyl)amino]benzyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[[4-[butyl(methylsulfonyl)amino]phenyl]methyl]-1,2-dihydro-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide-   1,2-dihydro-6-methyl-N-[[4-[(1-methylethyl)(methylsulfonyl)-amino]phenyl]methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide-   N-{4[(2-methoxyethyl)(methylsulfonyl)amino]benzyl}-6-methyl-2-oxo-1-[3    (trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-{4-[(2-cyanoethyl)(methylsulfonyl)amino]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-{4-[ethyl(methylsulfonyl)amino]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   1,2-dihydro-6-methyl-N-[[4-[(methylsulfonyl)propylamino)-phenyl]methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide-   N-[[4-[(3-amino-3-oxopropyl)(methylsulfonyl)amino]phenyl]-methyl]-1,2-dihydro-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide-   1,2-dihydro-6-methyl-N-[[4[(methylsulfonyl)oxy]phenyl]methyl]-2-oxo-1-(3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide-   2-propanesulfonic acid,    4-[[[[1,2-dihydro-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyridinyl]carbonyl]amino]methyl]phenyl    ester-   N-[(1,1-dioxido-2,3-dihydro-1-benzothien-5-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[(1,1-dioxido-2,3-dihydro-1-benzothien-5-yl)methyl]-5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   5-iodo-N-{4-[isopropyl(methylsulfonyl)amino]benzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   1,2-dihydro-6-methyl-N-[[4-[(methylsulfonyl)methyl]phenyl}-methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide-   6-chloro-5-methyl-4-(3-methylphenyl-N-[4-(methylsulfonyl)benzyl]-3-oxo-3,4-dihydropyrazine-2-carboxamide-   5-bromo-6-(difluoromethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-(difluoromethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-[3-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N′-[4-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carbohydrazide-   N′-(4-bromophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carbohydrazide-   N-[(5-methoxy-4-oxo-4H-pyran-2-yl)methyl]+methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(4-cyanobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-{[3-(4-methoxyphenyl)isoxazol-5-yl]methyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N′-(4-cyanophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydopyridine-3-carbohydrazide-   6-methyl-2-oxo-N-[(1-phenyl-1H-pyrazol-4-yl)methyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyrimidine-3-carboxamide-   N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-{[1-(3-methylphenyl)-1H-pyrazol-4-yl]methyl)-2-oxo-1-[3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide-   N′-(4-chlorophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carbohydrazide-   6-methyl-2-oxo-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[(4-benzylmorpholin-2-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyrimidine-3-carboxamide-   6-methyl-N-[(3-(2-methylpiperidin-1-yl)propyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   methyl    2-{[([{6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-yl}carbonyl)amino]methyl}-3-furoate-   6-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(3-azepan-1-ylpropyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-(3-morpholin-4-ylpropyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-(3-piperidin-1-ylpropyl)-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide-   N-[3-(3,5-dimethyl-1H-pyrazol-1-yl)propyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[3-(2-ethylpiperidin-1-yl)propyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-[2-(1-methyl-1H-imidazol-5-yl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[(1-ethyl-3-methyl-1H-pyrazol-4-yl)methyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[4-(acetylamino)benzyl]-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-[3-(1H-pyrazol-1-yl)propyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-(pyridin-2-ylmethyl)-1-(3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-{[1-(4-methylphenyl)-1H-pyrazol-4-yl]methyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N′-(4-methylphenyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carbohydrazide-   6-methyl-N-[3-(4-methylpiperidin-1-yl)propyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-[3-(5-oxo-4,5-dihydro-1H-pyrazol-4-yl)propyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   ethyl    5-methyl-4-([({6-methyl-2-oxo-1-(3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-yl}carbonyl)amino]methyl}-2-furoate-   N-[(6-fluoro-4H-1,3-benzodioxin-8-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-(2-pyridin-3-ylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[(1,3-dimethyl-1H-pyrazol    4-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-(2-pyridin-4-ylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N′-(4-fluorophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carbohydrazide-   6-methyl-N-[(1-methyl-1H-pyrrol-2-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N′-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carbohydrazide-   N-[(1-ethyl-5-methyl-1H-pyrazol-4-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-[2-(1-methyl-1H-imidazol-4-yl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[2-(1,3-dioxolan-2-yl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(1-benzothien-3-ylmethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[2-(3,5-dimethylisoxazol-4-yl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-(3,4-dihydro-1H-isochromen-1-ylmethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-{[(2R)-1-ethylpyrrolidin-2-yl]methyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-[(2R)-tetrahydrofuran-2-ylmethyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   5-chloro-N-{4-[(dimethylamino)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-{4-[(dimethylamino)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide-   5-chloro-6-methyl-2-oxo-N-[4-(piperazin-1-ylsulfonyl)benzyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-[4-(piperazin-1-ylsulfonyl)benzyl]-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-[4-(morpholin-4-ylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-[4-(piperidin-1-ylsulfonyl)benzyl]-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-(4-[(methylamino)sulfonyl]benzyl)-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-[4-(pyrrolidin-1-ylsulfonyl)benzyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   5-chloro    6-methyl-2-oxo-N-[pyrrolidin-1-ylsulfonyl)benzyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   5-chloro-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide-   N-{4-[(acetylamino)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[4-(isopropylsulfonyl)benzyl]-5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[4-(cyclopropylsulfonyl)benzyl]-5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydiopyridine-3-carboxamide-   1,2-dihydro-6-methyl-N-[[4-[(methylsulfonyl)oxy]phenyl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide-   N-[4-(1,1-dioxidoisothiazolidin-2-yl)benzyl]-6-methyl-2-oxo-1-(3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-[[4-(4-pyridinylsulfonyl)phenyl]methyl]-1-(3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-[4(phenylsulfonyl)benzyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-[4-(1,3-thiazol-2-ylsulfonyl)benzyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-2-oxo-N-[4-(pyrimidin-2-ylsulfonyl)benzyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[(1H-imidazol-2-ylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-{4-[(1-methyl-1H-1,2,4-triazol-5-yl)sulfonyl]benzyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-{4-[(5-methyl-1,3-oxazol-4-yl)sulfonyl]benzyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   6-methyl-N-{[6-(methylsulfonyl)pyridin-3-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   5-fluoro-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   N-[4-(methylsulfonyl)benzyl]-2-oxo-6-(2-oxoethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide-   5-ethyl-6-methyl-N-[4-methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide    and pharmaceutically acceptable salts thereof.

The present invention includes compounds of formula (I) in the form ofsalts, in particular acid addition salts. Suitable salts include thoseformed with both organic and inorganic acids. Such acid addition saltswill normally be pharmaceutically acceptable although salts ofnon-pharmaceutically acceptable acids may be of utility in thepreparation and purification of the compound in question. Thus,preferred salts include those formed from hydrochloric, hydrobromic,sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic,succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.

In a further aspect the invention provides a process for the preparationof a compound of formula (I) which comprises:

-   reacting a compound of formula (II)    wherein R¹, R⁵, Y¹, Y², X, G¹ and n are as defined in formula (I)    and L¹ represents a leaving group,    with an amine of formula (III) or a salt thereof    wherein R⁴, G² and L are as defined in formula (I),    and where desired or necessary converting the resultant compound of    formula (I), or another salt thereof, into a pharmaceutically    acceptable salt thereof; or converting one compound of formula (I)    into another compound of formula (I); and where desired converting    the resultant compound of formula (I) into an optical isomer    thereof.

The process is carried out at a suitable temperature, generally between0° C. and the boiling point of the solvent, in a suitable solvent suchas dichloromethane or N-methylpyrrolidinone. The process is optionallycarried out in the presence of a base and/or a coupling reagent such asHATU, HOAT, HOBT or DIEA. Suitable leaving groups L¹ include OH andhalogen, particularly OH.

Compounds of formula (II) wherein Y¹ is CR², Y² is CR³, L¹ is OH and R²and R² are both hydrogen can be prepared by condensing a compound offormula (IV)

wherein R¹ is as defined in formula (I),with a compound of formula (V)

wherein G¹, R⁵ and n are as defined in formula (I), in the presence of asuitable base, such as sodium methoxide, in a suitable solvent, such asethanol, followed by hydrolysis using a suitable base such as sodiumhydroxide.

In general, compounds of formulae (IV) and (V) are either known or maybe prepared using methods that will be readily apparent to the manskilled in the art. For example, compounds of formula (IV) can beprepared according to the methods of S. M. Brombridge et al., SyntheticCommunications, 1993, 23, 487494. And compounds of formula (V) can beprepared according to the methods of Igor V. Ukrainets et al.,Tetrahedron, 1994, 50, 10331-10338.

Compounds of formula (II) wherein Y¹ is CR², Y¹ is CR³, L¹ is OH and R¹is hydrogen can be prepared by reacting a compound of formula (VI)

wherein G¹, R⁵ and n are as defined in formula (I), with a compound offormula (VII)

wherein R² or R³ are as defined in formula (I), at a suitabletemperature, such as 160° C., followed by base promoted cyclisation andacid hydrolysis. Compounds of formula (VII) can be prepared according toU.S. Pat. No. 3,838,155.

Compounds of formula (II) wherein Y¹ is CR¹, Y² is CR², L¹ is OH, R² ismethyl and R² and R³ are both hydrogen can be prepared by condensing acompound of formula (VII)

wherein G¹, R⁵ and n are as defined in formula (I), with4-methoxy-3-buten-2-one in the presence of a suitable base, such as1,4-diazabicyclo[2,2,2]octane, at a suitable temperature in a suitablesolvent such as diethyleneglycol monomethyl ether, followed by acid ishydrolysis.

Compounds of formula (II) wherein R¹ is OH, Y¹ is nitrogen and Y² is CR³can be prepared by condensing a compound of formula (IX)

wherein G¹, R⁵ and n are as defined in formula (I), with a compound offormula (X)

in the presence of a suitable base, such as sodium ethoxide, at asuitable temperature in a suitable solvent such as ethanol.

A compound of formula (IX) can be prepared from the correspondingisocyanate derivative by treatment with ammonia in acetonitrile.

Salts of compounds of formula (I) may be formed by reacting the freebase or a salt, enantiomer, tautomer or protected derivative thereof,with one or more equivalents of the appropriate acid. The reaction maybe carried out in a solvent or medium in which the salt is insoluble, orin a solvent in which the salt is soluble followed by subsequent removalof the solvent in vacuo or by freeze drying. Suitable solvents include,for example, water, dioxane, ethanol, 2-propanol, tetrahydrofuran ordiethyl ether, or mixtures thereof. The reaction may be a metatheticalprocess or it may be carried out on an ion exchange resin.

Compounds of formula (I) and intermediate compounds thereto may beprepared as such or in protected form. The protection and deprotectionof functional groups is, for example, described in ‘Protective Groups inOrganic Chemistry’, edited by J. W. F. McOmie, Plenum Press (1973), and‘Protective Groups in Organic Synthesis’, 3rd edition, T. W. Greene & P.G. M. Wuts, Wiley-Interscience (1999).

The compounds of the invention and intermediates may be isolated fromtheir reaction mixtures, and if necessary further purified, by usingstandard techniques.

The compounds of formula (I) may exist in enantiomeric ordiastereoisomeric forms or mixtures thereof, all of which are includedwithin the scope of the invention. The various optical isomers may beisolated by separation of a racemic mixture of the compounds usingconventional techniques, for example, fractional crystallisation orHPLC. Alternatively, the individual enantiomers may be made by reactionof the appropriate optically active starting materials under reactionconditions that will not cause racemisation.

Intermediate compounds may also exist in enantiomeric forms and may beused as purified enantiomers, diastereomers, racemates or mixturesthereof.

According to a further aspect of the invention we provide a compound offormula (I) or a pharmaceutically acceptable salt thereof, for use as amedicament.

The compounds of formula (I), and their pharmaceutically acceptablesalts, are useful because they possess pharmacological activity inanimals. The compounds of formula (I) have activity as pharmaceuticals,in particular as modulators of human neutrophil elastase and homologousserine proteases such as proteinase 3 and pancreatic elastase, and assuch are predicted to be useful in therapy. The compounds of formula (I)are particularly useful as inhibitors of human neutrophil elastase. Theymay thus be used in the treatment or prophylaxis of inflammatorydiseases and conditions.

Examples of these conditions are: adult respiratory distress syndrome(ARDS), cystic fibrosis, pulmonary emphysema, chronic obstructivepulmonary disease (COPD) and ischaemic-reperfusion injury. The compoundsof this invention may also be useful in the modulation of endogenousand/or exogenous biological irritants which cause and/or propagateatherosclerosis, diabetes, myocardial infarction; hepatic disordersincluding but not limited to cirrhosis, systemic lupus erythematous,inflammatory disease of lymphoid origin, including but not limited to Tlymphocytes, B lymphocytes, thymocytes; autoimmune diseases, bonemarrow; inflammation of the joint (especially rheumatoid arthritis,osteoarthritis and gout); inflammation of the gastrointestinal tract(especially inflammatory bowel disease, ulcerative colitis, pancreatitisand gastritis); inflammation of the skin (especially psoriasis, eczema,dermatitis); in tumour metastasis or invasion; in disease associatedwith uncontrolled degradation of the extracellular matrix such asosteoarthritis; in bone resorptive disease (such as osteoporosis andPaget's disease); diseases associated with aberrant angiogenesis; theenhanced collagen remodelling associated with diabetes, periodontaldisease (such as gingivitis), corneal ulceration, ulceration of theskin, post-operative conditions (such as colonic anastomosis) and dermalwound healing; demyelinating diseases of the central and peripheralnervous systems (such as multiple sclerosis); age related illness suchas dementia, inflammatory diseases of cardiovascular origins;granulomatous diseases; renal diseases including but not limited tonephritis and polyarteritis; cancer; pulmonary hypertension, ingestedpoisons, skin contacts, stings, bites; asthma; rhinitis; HIV diseaseprogression; for minimising the effects of organ rejection in organtransplantation including but not limited to human organs; andreplacement therapy of proteinase inhibitors.

Thus, another aspect of the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment or prophylaxis of diseasesor conditions in which inhibition of neutrophil elastase activity isbeneficial; and a method of treating, or reducing the risk of, diseasesor conditions in which inhibition of neutrophil elastase activity isbeneficial which comprises administering to a person suffering from orat risk of, said disease or condition, a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment or prophylaxis ofinflammatory diseases or conditions; and a method of treating, orreducing the risk of, inflammatory diseases or conditions whichcomprises administering to a person suffering from or at risk of, saiddisease or condition, a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof.

In particular, the compounds of this invention may be used in thetreatment of adult respiratory distress syndrome (ARDS), cysticfibrosis, pulmonary emphysema, chronic obstructive pulmonary disease(COPD), pulmonary hypertension, asthma, rhinitis, ischemia-reperfusioninjury, rheumatoid arthritis, osteoarthritis, cancer, atherosclerosisand gastric mucosal injury.

Prophylaxis is expected to be particularly relevant to the treatment ofpersons who have suffered a previous episode of, or are otherwiseconsidered to be at increased risk of, the disease or condition inquestion. Persons at risk of developing a particular disease or iscondition generally include those having a family history of the diseaseor condition, or those who have been identified by genetic testing orscreening to be particularly susceptible to developing the disease orcondition.

For the above mentioned therapeutic indications, the dose of thecompound to be administered will depend on the compound employed, thedisease being treated, the mode of administration, the age, weight andsex of the patient. Such factors may be determined by the attendingphysician. However, in general, satisfactory results are obtained whenthe compounds are administered to a human at a daily dosage of between0.1 mg/kg to 100 mg/kg (measured as the active ingredient).

The compounds of formula (I) may be used on their own, or in the form ofappropriate pharmaceutical formulations comprising the compound of theinvention in combination with a pharmaceutically acceptable diluent,adjuvant or carrier. Particularly preferred are compositions notcontaining material capable of causing an adverse reaction, for example,an allergic reaction. Conventional procedures for the selection andpreparation of suitable pharmaceutical formulations are described in,for example, “Pharmaceuticals—The Science of Dosage Form Designs”, M. E.Aulton, Churchill Livingstone, 1988.

According to the invention, there is provided a pharmaceuticalformulation comprising preferably less than 95% by weight and morepreferably less than 50% by weight of a compound of formula (I) inadmixture with a pharmaceutically acceptable diluent or carrier.

We also provide a method of preparation of such pharmaceuticalformulations that comprises mixing the ingredients.

The compounds may be administered topically, for example, to the lungsand/or the airways, in the form of solutions, suspensions, HFA aerosolsor dry powder formulations, for example, formulations in the inhalerdevice known as the Turbuhaler®; or systemically, for example, by oraladministration in the form of tablets, pills, capsules, syrups, powdersor granules; or by parenteral administration, for example, in the formof sterile parenteral solutions or suspensions; or by rectaladministration, for example, in the form of suppositories.

Dry powder formulations and pressurized HFA aerosols of the compounds ofthe invention may be administered by oral or nasal inhalation. Forinhalation, the compound is desirably finely divided. The finely dividedcompound preferably has a mass median diameter of less than 10 μm, andmay be suspended in a propellant mixture with the assistance of adispersant, such as a C₈-C₂₀ fatty acid or salt thereof, (for example,oleic acid), a bile salt, a phospholipid, an alkyl saccharide, aperfluorinated or polyethoxylated surfactant, or other pharmaceuticallyacceptable dispersant.

The compounds of the invention may also be administered by means of adry powder inhaler. The inhaler may be a single or a multi dose inhaler,and may be a breath actuated dry powder inhaler.

One possibility is to mix the finely divided compound with a carriersubstance, for example, a mono-, di- or polysaccharide, a sugar alcohol,or an other polyol. Suitable carriers are sugars, for example, lactose,glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose,mannitol; and starch. Alternatively the finely divided compound may becoated by another substance. The powder mixture may also be dispensedinto hard gelatine capsules, each containing the desired dose of theactive compound.

Another possibility is to process the finely divided powder into sphereswhich break up during the inhalation procedure. This spheronized powdermay be filled into the drug reservoir of a multidose inhaler, forexample, that known as the Turbuhaler® in which a dosing unit meters thedesired dose which is then inhaled by the patient. With this system theactive compound, with or without a carrier substance, is delivered tothe patient.

For oral administration the active compound may be admixed with anadjuvant or a carrier, for example, lactose, saccharose, sorbitol,mannitol; a starch, for example, potato starch, corn starch oramylopectin; a cellulose derivative; a binder, for example, gelatine orpolyvinylpyrrolidone; and/or a lubricant, for example, magnesiumstearate, calcium stearate, polyethylene glycol, a wax, paraffin, andthe like, and then compressed into tablets. If coated tablets arerequired, the cores, prepared as described above, may be coated with aconcentrated sugar solution which may contain, for example, gum arabic,gelatine, talcum, titanium dioxide, and the like. Alternatively, thetablet may be coated with a suitable polymer dissolved in a readilyvolatile organic solvent.

For the preparation of soft gelatine capsules, the compound may beadmixed with, for example, a vegetable oil or polyethylene glycol. Hardgelatine capsules may contain granules of the compound using either theabove mentioned excipients for tablets. Also liquid or semnisolidformulations of the drug may be filled into hard gelatine capsules.

Liquid preparations for oral application may be in the form of syrups orsuspensions, for example, solutions containing the compound, the balancebeing sugar and a mixture of ethanol, water, glycerol and propyleneglycol. Optionally such liquid preparations may contain colouringagents, flavouring agents, saccharine and/or carboxymethylcellulose as athickening agent or other excipients known to those sied in art.

The compounds of the invention may also be administered in conjunctionwith other compounds used for the treatment of the above conditions.

The following Examples are intended to illustrate, but in no way limitthe scope of the invention.

General Procedures

¹H NMR and ¹³C NMR were recorded on a Varian Inova 400 MHz or a VarianMercury-VX 300 MHz instrument. The central peaks of chloroform-d (δ_(H)7.27 ppm), dimethylsulfoxide-d₆ (δ_(H) 2.50 ppm), acetonitrile-d₃ (δ_(H)1.95 ppm) or inethanol-d₄ (δ_(H) 3.31 ppm) where used as internalreferences. Low-resolution mass spectra were obtained on an Agilent 100LC-MS system equipped with an APCI ionisation chamber. Columnchromatography was carried out using silica gel (0.040-0.063 mm, Merck).Unless stated otherwise, starting materials were commercially available.All solvents and commercial reagents were of laboratory grade and wereused as received. Unless otherwise stated, organic solutions were driedusing anhydrous Na₂SO₄.

Unless otherwise stated, the following methods were used for HPLC andLC/MS analysis:

LC/MS-Method A

Instrument Agilent 1100; Column Waters Symmetry 2.1×30 mm; Mass APCI;Flow rate 0.7 ml/in; Wavelength 254 nm; Solvent A: Water+0.1% TFA; B:Acetonitrile +0.1% TFA; Gradient 15-95%/B 8 min, 95% B 1 min.

LC-Method B

Instrument Agilent 1100; Column KR100-5C18 150×4.6 mm; Flow rate 1.0ml/min; Wavelength 220 nm; Solvent A: Water+0.1% TPA; B: Acetonitxile+0.1% TPA; Gradient 20-100%/B 8 min 100% B 2 nm.

The following abbreviations are used:

-   HBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBT 1-Hydroxybenzotriazole-   HOAT 1-Hydroxy-7-azabenzotriazole-   DIEA N,N-Diisopropylethylamine-   NMP 1-N-Methyl-2-pyrrolidinone-   THP Tetrahydrofuran-   TFA Trifluoroacetic acid

EXAMPLE 1N-(4-Chlorobenzyl)-1-(4-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamidea) Ethyl 3-[(4-chlorophenyl)amino]-3-oxopropanoate

The title compound was prepared essentially as described by L V.Ukrainets et al., Tetrahedron, 1994, 50, 10331-10338.

b) Ethyl1-(4-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate

A mixture of ethyl 3-[(4-chlorophenyl)amino]-3-oxopropanoate (1 g, 4mmol), 4-methoxy-3-buten-2-one (0.42 g, 4.2 mmol) and sodium methoxide(0.22 g, 4.1 mmol) in ethanol (10 ml) was heated to reflux for 5 h.After cooling, the solvent was evaporated off. The residue waschromatographed on silica using heptane/ethyl acetate (1:1 to 1:5) aseluent, affording the title compound (297 mg, 25%).

¹HNMR (CDCl₃): δ 8.17 (1H, d); 7.49 (2H, d); 7.13 (2H, d); 6.21 (1H, d);4.34 (2H q); 2.03 (3H, s); 1.35 (3H, t).

c) 1-(4-Chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylicacid

Ethyl1-(4-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (297mg, 1.0 mmol) was dissolved in a mixture of 1M sodium hydroxide solution(6 ml) and THF (5 ml). The reaction mixture was stirred for 2.5 h atroom temperature, then acidified to pH 2 using 5M hydrochloric acid, andthen extracted with dichloromethane. The combined organic phases werewashed with water, dried, filtered and evaporated to give the titlecompound (268 mg, 100%).

¹H NMR (CDCl₃): δ 8.51 (1H, d); 7.59 (2H, d); 7.18 (2H, d); 6.53 (1H,d); 2.15 (3H, s).

d)N-(4-Chlorobenzyl)-1-(4-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

A mixture of1-(4-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid(100 mg, 0.38 mmol), HBTU (59 mg, 0.42 mmol), HOBT (64 mg, 0.42 mmol)and DIEA (195 μl, 1.14 mmol) in NMP (1 ml) was added to4-chlorobenzylamine (108 mg, 0.76 mmol) in NMP (0.5 μl). The reactionmixture was stirred for 18 h. The solvent was evaporated off and theresidue was purified using preparative HPLC to give the title compound(60 mg, 41%).

¹H NMR (CDCl₃): δ 9.91 (1H, brs); 8.54 (1H, d); 7.53 (2H, d); 7.24 (4H,s); 7.13 (2H, d); 6.42 (1H, d); 4.53 (2H, d); 2.07 (3H, s).

Using the general method described in Example 1, the compounds ofExamples 1.1 to 1.27 were prepared:

Example 1.16-Methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.96 (1H, t); 8.57 (1H, d); 7.85 (2H, d); 7.80 (1H,d); 7.73 (1H, t); 7.50 (3H, brd); 7.42 (1H, d); 6.46 (1H, d); 4.65 (2H,d); 3.00 (3H, s); 2.07 (3H, s).

Example 1.26-Methyl-N-(4-morpholin-4-ylbenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (DMSO-d₆): δ 9.69 (1H, brt); 8.38 (1H d); 7.89-7.87 (2H, m); 7.79(1H, t); 7.70 (1H, d); 7.15 (2H, d); 6.87 (2H, d); 6.62 (1H, d); 4.36(2H, d); 3.72-3.69 (4H, m) 3.05-3.03; (4H, m); 2.00 (3H, s).

APCI-MS m/z: 472 [MH⁺].

Example 1.36-Methyl-N-[4-(methylsulfonyl)phenyl]-1,2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 12.00 (1H, s); 8.66 (1H, d); 7.92-7.85 (5H, m); 7.79(1H, t); 7.56 (1H, s); 7.49 (1H, d); 6.55 (1H, d); 3.04 (3H, s); 2.13(3H, s).

APCI-MS m/z: 451[MH⁺].

Example 1.4N-[4-(Dimethylamino)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.67 (1H, brs); 8.57 (1H, d); 7.78 (1H, d); 7.71 (1H,t); 7.49 (1H, s); 7.41 (1H, d); 7.21 (2H, brd); 6.72 (2H, brs); 6.43(1H, d); 4.50 (2H, d); 2.91 (6H, s); 2.05 (3H, s).

Example 1.5N-[4-(Aminosulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹HNMR (MSO-d₆): δ 9.89 (1H, brs); 8.37 (1H, d); 7.91 (1H, s); 7.89 (1H,d); 7.80 (1H, t); 7.75 (2H, d); 7.72 (1H, d); 7.45 (2H, d); 7.27 (2H,s); 6.62 (1H, d); 4.54 (2H, s); 2.02 (3H, s).

Example 1.6N-(4-Methoxybenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.72 (1H, brs); 8.59 (1H, d); 7.79 (1H, d); 7.72 (1H,t); 7.49 (1H, s); 7.42 (1H, d); 7.24 (2H, d); 6.82 (2H, d); 6.44 (1H,d); 4.52 (2H, d); 3.76 (3H, s); 2.05 (3H, s).

Example 1.7N-Benzyl-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.85 (1H, brs); 8.62 (1H, d); 7.81 (1H, d); 7.74 (1H,t); 7.52 (1H, s); 7.44 (1H, d); 7.36-7.21 (5H, m); 6.47 (1H, d); 4.61(2H, d); 2.08 (3H, s).

Example 1.8N-(4-Chlorobenzyl-1-(2-fluoro-5-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CD₃OD): δ 8.48 (1H, d); 7.40-7.36 (1 m); 7.30 (4H, s); 7.25 (1H,t); 7.19 (1H, dd); 6.62 (1H, d); 4.56 (2H, q); 2.39 (3H, s); 2.13 (3H,s).

Example 1.9N-(3-Chlorobenzyl)-1-(2-fluoro-5-methylphenyl)-6-methyl-2-oxo1,2-dihydropyridine-3-carboxamide

¹H NMR (CD₃OD): δ 8.48 (1H, d); 7.40-7.36 (1H, m); 7.33-7.32 (1H, m);7.29-7.22 (4H, m); 7.20 (1H, dd); 6.62 (1, d); 4.57 (2H q); 2.39 (3H,s); 2.13 (3H, s).

Example 1.101-(2-Fluoro-5-methylphenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CD₃OD): δ 8.48 (1H, d); 7.40-7.36 (1H, m); 7.27-7.21 (3H, m);7.02 (1H, dd); 6.86 (2H, d); 6.62 (1H, d); 4.50 (2H, q); 3.75 (3H, s);2.39 (3H, s); 2.12 (3H, s).

APCI-MS m/z: 381 [MH⁺].

Example 1.11N-(4-Methoxybenzyl)-1-(3-methoxyphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.86 (1H, brs); 8.54 (1H, d); 7.45 (1H, t); 7.23 (2H,d); 7.04-7.01 (1H, m); 6.80 (2H, d); 6.78-6.75 (1H, m); 6.70 (1H, t);6.39 (1H, d); 4.51 (2H, d); 3.82 (3H, s); 3.76 (3H, s); 2.09 (3H, s).

APCI-MS m/z: 379 [MH⁺].

Example 1.12N-(3-Chlorobenzyl)-1-(3-methoxyphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.00 (1H, brs); 8.55 (1H, d); 7.47 (1H, t); 7.30 (1H,brs); 7.19 (3H, brs); 7.05-7.01 (1×, m); 6.806.75 (1H, m); 6.72 (1H, t);6.41 (1H, d); 4.55 (2H, d); 3.83 (3H, s); 2.11 (3H, s).

Example 1.13 N-(6-Chlorobenzyl)-1-(3-methoxyphenyl)-6-methyl-2-oxo 1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.00 (1H, brs); 8.56 (1H, d); 7.48 (1H, t); 7.28 (4H,s); 7.07-7.03 (1H, m); 6.81-6.77 (1H, m); 6.73 (1H, t); 6.41 (1H, d);4.56 (2H, d); 3.85 (3H, s); 2.12 (3H, s).

Example 1.14N-[4-(Aminosulfonyl)benzyl]-1-(3-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.99 (1H, t); 8.55 (1H, d); 7.84 (2H, d); 7.53-7.49(2H, m); 7.46 (1H, d); 7.25-7.24 (1H, m); 7.14-7.10 (1H, m); 6.44 (1H,d); 4.72 (2H, brs); 4.64 (2H, d); 2.10 (3H, s).

Example 1.15N-(4-Chlorobenzyl)-1-(3-chloro-4-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.93 (1H, brs); 8.56 (1H, d); 7.44 (1H, d); 7.28 (4H,s); 7.24 (1H, d); 7.03 (1H, dd); 6.43 (1H, d); 4.56 (2H, d); 2.46 (3H,s); 2.12 (3H, s).

Example 1.161-(3-Chloro-4-methylphenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.80 (1H, brs); 8.54 (1H, d); 7.40 (1H, d); 7.23 (2H,d); 7.20 (1H, d); 7.00 (1H, dd); 6.81 (2H, d); 6.39 (1H, d); 4.51 (2H,d); 3.76 (3H, s); 2.43 (3H, s); 2.09 (3H, s).

Example 1.17N-(4-Chlorobenzyl)1-(23-dimethylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.04 (1H, brs); 8.58 (1H, d); 7.31-7.24 (6H, m);6.96-6.94 (1H, m); 6.45 (1H, d); 4.634.50 (2H, m); 2.38 (3H, s); 2.03(3H, s); 1.95 (3H, s).

Example 1.18N-(4-Chlorobenzyl)-1-(3-chloro-4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹HNMR (CDCl₃): δ 9.83 (1H, brs); 8.57 (1H, d); 7.38-732 (2H, m); 7.27(4H, s); 7.15-7.11 (1H, m); 6.45 (1H, d); 4.57 (2H, d); 2.12 (3H, s).

APCI-MS m/z: 405.1, 407 [MH⁺].

Example 1.191-(3-Chloro-4-fluorophenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.72 (1H, brs); 8.58 (1H, d); 7.39-7.31 (2H, m); 7.26(2H, d); 7.14-7.10 (1H, m); 6.84 (2H, d); 6.43 (1H, d); 4.54 (2H, d);3.79 (3H, s); 2.11 (3H, s).

Example 1.20N-(4-Chlorobenzyl)-1-(3-ethylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.03 (1H, brs); 8.56 (1H, d); 7.49 (1H, t); 7.36 (1H,d); 7.28 (4H, s); 7.02 (2H, d); 6.42 (1H, d); 4.614.50 (2H, m); 2.75(2H, q); 2.09 (3H, s); 1.29 (3H, t).

Example 1.21 1-(3-Bromophenyl)-N-(4-chlorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.86 (1H, brs); 8.55 (1H, d); 7.67-7.64 (1H, m); 7.45(1H, t); 7.39 (1H, t); 7.25 (4H, s); 7.17-7.15 (1H, m); 6.42 (1H, d);4.54 (2H, d); 2.09 (3H, s).

APCI-MS m/z: 431.1, 433 [MH ⁺]

Example 1.221-(3-Bromophenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.74 (1H, brs); 8.55 (1H, d); 7.65-7.63 (1H, m); 7.44(1H, t); 7.38 (1H, t); 7.23 (2H, d); 7.16-7.14 (1H, m); 6.81 (2H, d);6.40 (1H, d); 4.52 (2H, d); 3.76 (3H, s); 2.07 (3H, s).

Example 1.23N-(2.3-Dihydro-1-benzofuran-5-ylmethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.70 (1H, brs); 8.59 (1H, d); 7.79 (1H, d); 7.73 (1H,t); 7.50 (1H, s); 7.43 (1H, d); 7.17 (1H, s); 7.05 (1H, d); 6.69 (1H,d); 6.44 (1H, d); 4.56-4.50 (4H, m); 3.16 (2H, t); 2.06 (3H, s).

APCI-MS m/z: 429 [MH⁺].

Example 1.246-Methyl-2-oxo-N-[3-(2-oxopyrrolidin-1-yl)propyl]-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

¹HNMR (CDCl₃): δ 9.55 (1H, brs); 8.55 (1H, d); 7.82 (1×, d); 7.75 (1 t);7.52 (1H, s); 7.45 (1H, d); 6.45 (1H, d); 3.44-3.33 (6H, m); 2.38 (2H,t); 2.05-1.98 (2H, m); 2.08 (3H, s); 1.86-1.79 (2H, m).

APCI-MS m/z: 422 [MH⁺].

Example 1.25N-(4-Bromobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.84 (1H, brs); 8.58 (1H, d); 7.81 (1H, d); 7.73 (1H,t); 7.51 (1H, s); 7.43 (1H, d); 7.41 (2H, d); 7.20 (2H, d); 6.46 (1H,d); 4.594.49 (2H, m); 2.08 (3H, s).

APCI-MS m/z: 465.1, 467 [MH⁺].

Example 1.26N-(4-Chlorophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 407 [MH⁺].

Example 1.276-Methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 297 [MH⁺].

EXAMPLE 2N-(4-Methoxybenzyl)-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamidea) 6-Methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carbonitrile

A mixture of cyanoacetanilide (0.80 g, 5 mmol), 4-methoxy-3-buten-2-one(1 g, 10 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.55 g, 5 mmol) indiethyleneglycol monomethylether was heated to 125° C. for 5 h. Thereaction mixture was partitioned between dichloromethane (100 ml) and 2Mhydrochloric acid (100 ml). The organic layer was separated, washed withwater, dried, filtered and evaporated. The residue was chromatographedon silica using heptane/ethyl acetate (1:1) as eluent, affording thetitle compound (660 mg, 63%).

¹H NMR (CDCl₃): δ 7.78 (1H, d); 7.52 (3H, m); 7.17 (2H, dd); 6.22 (1H,d); 2.06 (3H, s).

b) 6-Methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid

6-Methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carbonitrile (300 mg, 1.4mmol) was dissolved in 2.5M sulphuric acid (10 ml). The mixture washeated to 100° C. for 16 h. After cooling, the solution was poured intowater and made alkaline with 5M sodium hydroxide solution. The waterphase was washed with dichloromethane, then acidified to pH 2-3 using 2Mhydrochloric acid. The acidified water phase was extracted withdichloromethane, dried, filtered and evaporated to give the titlecompound (300 mg, 92%).

¹H NMR (CDCl₃): δ 13.96 (1H, s); 8.50 (1H, d); 7.59 (3H, m); 7.23 (2H,dd); 6.53 (1H, d); 2.13 (3H, s).

c)N-(4-Methoxybenzyl)-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

The title compound was prepared from6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid and4-methoxybenzyl amine by a method analogous to that described in Example1 step (d).

¹H NMR (CDCl₃): δ 9.87 (1H, brs); 8.56 (1H, brd); 7.52 (3H, m); 7.23(2H, d); 7.18 (2H, d); 6.79 (2H, d); 6.40 (1H, d); 4.51 (2H, d); 3.75(3H, s); 2.04 (3H, s).

The compounds of Examples 2.1 to 2.174 were prepared by a methodanalogous to that described in Example 1 or 2.

Example 2.1N-(4-Chlorobenzyl)-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.96 (1H, s); 8.54 (1H, d); 7.54 (3H, m); 7.23 (4H,s); 7.18 (2H, d); 6.41 (1H, d); 4.54 (2H, d); 2.06 (3H, s).

Example 2.2N-(4-Chlorobenzyl)-1-(3,5-dimethylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.01 (1H, brs); 8.52 (1H, d); 7.23 (4H, s); 7.11 (1H,s); 6.78 (2H, s); 6.38 (1H, d); 4.53 (2H, d); 2.36 (6H, s); 2.07 (3H,s).

Example 2.3N-[4-(Aminosulfonyl)benzyl]-1-(3,5-dimethylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.14 (1H, brs); 8.51 (1H, d); 7.82 (2H, d); 7.45 (2H,d); 7.12 (1H, s); 6.79 (2H, s); 6.41 (1H, d); 4.72 (2H, s); 4.62 (2H,d); 2.36 (6H, s); 2.09 (3H, s).

Example 2.41-(3.5-Dimethylphenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.90 (1H, brs); 8.54 (1H, d); 724 (2H, s); 7.11 (1H,s); 6.81 (2H, d); 6.79 (2H, s); 6.38 (1H, d); 4.52 (2H, d); 3.77 (3H,s); 2.37 (6H, s); 2.07 (3H, s).

Example 2.5N-Benzyl-1-(3.5-dimethylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.98 (1H, brs); 8.57 (1H, d); 7.36-7.19 (5H, m); 7.13(1H, s); 6.82 (2H, s); 6.41 (1H, d); 4.61 (2H, d); 2.39 (6H, s); 2.10(3H, s).

Example 2.6N-(4-Chlorobenzyl)-6-methyl-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CD₃OD): δ 8.46 (1H, d); 7.47 (1H, t); 736 (1H, d); 7.30 (4H, s);7.10 (1H, s); 7.06 (1H, d); 6.60 (1H, d); 4.56 (2H, s); 2.42 (3H, s);2.09 (3H, s).

APCI-MS m/z: 367 [MH⁺].

Example 2.7N-(4-Methoxybenzyl)-6-methyl-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CD₃OD): δ 8.45 (1H, d); 7.44 (1H, t); 7.33, (1H, d); 7.22 (2H,d); 7.07 (1H, s); 7.03 (1H, d); 6.84 (2H, d); 6.58 (1H, d); 4.49 (2H,s); 3.74 (3H, s); 2.41 (3H, s); 2.07 (3H, s).

APCI-MS m/z: 363 [MH⁺].

Example 2.8N-(3-Chlorobenzyl)-6-methyl-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CD₃OD): δ 8.46 (1H, d); 7.46 (1H, t); 7.35 (1H, d); 7.32-7.21(4H, m); 7.10 (1H, s); 7.06 (1H, d); 6.60 (1H, d); 4.56 (2H, s); 2.42(3H, s); 2.09 (3H, s).

Example 2.9N-(4-Chlorobenzyl)-1-(3-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (DMSO-d₆): δ 9.86 (1H, t); 8.35 (1H, d); 7.59-7.58 (3H, m);7.39-7.29 (5H, m); 6.60 (1H, d); 4.46 (2H, d); 2.04 (3H, s).

APCI-MS m/z: 387.1, 389 [MH⁺].

Example 2.10N-(3-Chlorobenzyl)-1-(3-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (DMSO-d₆): δ 9.88 (1H, t); 8.36 (1H, d); 7.59-7.58 (3H, m);7.39-7.32 (4H, m); 7.25 (1H, d); 6.60 (1H, d); 4.48 (2H, d); 2.04 (3H,s).

APCI-MS m/z: 387.1, 389 [MH⁺].

Example 2.111-(3-Chlorophenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (DRMSO-d₆): δ 9.73 (1H, t); 8.34 (1H, d); 7.56 (2H, d); 7.34-7.31(1H, m); 7.19 (2H, d); 6.85 (2H, d); 6.58 (1H, d); 6.60 (1H, d); 4.38(2H, d); 3.69 (3H, s); 2.01 (3H, s).

APCI-MS m/z: 383 [MH⁺].

Example 2.12 Methyl4-[({[1-(3-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl]carbonyl}amino)methyl]benzoate

¹H NMR (DMSO-d₆): δ 9.92 (1H, t); 8.36 (1H, d); 7.91 (2H, d); 7.60-7.58(3H, m); 7.41 (2H, d); 7.38-7.35 (1H, m); 6.60 (1H, d); 4.56 (2H, d);3.83 (3H, s); 2.04 (3H, s).

APCI-MS m/z: 411 [MH⁺].

Example 2.134-[({[1-(3-Chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl]carbonyl}amino)methyl]benzoicacid

¹H NMR (DMSO-d₆): δ 12.82 (1H, brs); 9.91 (1H, t); 8.36 (1H, d); 7.88(2H, d); 7.59-7.58 (3H, m); 7.39 (2H, d); 7.38-7.35 (1H, m); 6.60 (1H,d); 4.55 (2H, d); 2.04 (3H, s).

APCI-MS m/z: 397 [MH⁺].

Example 2.141-(3-Cyanophenyl)-N-(cyclohexylmethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 350 [MH⁺].

Example 2.151-(3-Cyanophenyl)-N-(2-furylmethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 334 [MH⁺].

Example 2.161-(3-Cyanophenyl)-6-methyl-2-oxo-N-(pyridin-3-ylmethyl)-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 345 [MH⁺].

Example 2.17N-Benzyl-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 344 [MH⁺].

Example 2.181-[3-Cyanophenyl)-N-2,3-dihydro-1H-inden-1-yl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 370 [MH⁺].

Example 2.191-(3-Cyanophenyl)-N-(2-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 374 [MH⁺].

Example 2.201-(3-Cyanophenyl)-6-methyl-2-oxo-N-(3,4,5-trimethoxybenzyl)-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 434 [MH⁺].

Example 2.211-(3-Cyanophenyl)-N-(2,5-dimethoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 404 [MH⁺].

Example 2.221-(3-Cyanophenyl)-N-(3.4-dimethoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 404 [MH⁺];

Example 2.231-(3-Cyanophenyl)-N-[(1-ethylprrolidin-2-yl)methyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 365 [MH⁺].

Example 2.24N-(4-Chlorobenzyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 378 [MH⁺].

Example 2.251-(3-Cyanophenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 374 [MH⁺].

Example 2.26N-(3-Chlorobenzyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 378 [MH⁺].

Example 2.271-(3-Cyanophenyl)-6-methyl-2-oxo-N-(thien-2-ylmethyl)-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 350 [MH⁺].

Example 2.281-(3-Cyanophenyl)-N-(cyclopropylmethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 308 [MH⁺].

Example 2.291-(3-Cyanophenyl)-N-(3-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 374 [MH⁺].

Example 2.301-(3-Cyanophenyl)-6-methyl-2-oxo-N-(pyridin-4-ylmethyl)-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 345 [MH⁺].

Example 2.311-(3-Cyanophenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 417 [MH⁺].

Example 2.321-(3-Cyanophenyl)-6-methyl-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 365 [MH⁺].

Example 2.33N-[2-(3-Chlorophenyl)ethyl]-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 392 [MH⁺].

Example 2.341-(3-Cyanophenyl)-6-methyl-2-oxo-N-(2-pyridin-2-ylethyl)-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 359 [MH⁺].

Example 2.35N-[2-(4-Chlorophenyl)ethyl]-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 392 [MH⁺].

Example 2.361-(3-Cyanophenyl)-N-[2-(2-methoxyphenyl)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 388 [MH⁺].

Example 2.37N-[2-(2-Chlorophenyl)ethyl]-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 392 [MH⁺].

Example 2.381-(3-Cyanophenyl)-N-[2-(3-methoxyphenyl)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 388 [MH⁺].

Example 2.391-(3-Cyanophenyl)-N-[2-(4-fluorophenyl)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 376 [MH⁺].

Example 2.401-(3-Cyanophenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 426 [MH⁺].

Example 2.411-(3-Cyanophenyl)-N-[2-(3-fluorophenyl)ethyl]methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 376 [MH⁺].

Example 2.421-(3-Cyanophenyl)-N-[2-(2-fluorophenyl)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 376 [MH⁺].

Example 2.43 1-(3-Cyanohenyl)-N-(2-cyclohex-1-en-1-ylethyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 362 [MH⁺].

Example 2.44N-[2-(4-Bromophenyl)ethyl]-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 438 [MH⁺].

Example 2.45N-(3-Bromobenzyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 424 [MH⁺].

Example 2.46N-(4-Bromobenzyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 424 [MH⁺].

Example 2.47N-(2-Bromobenzyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 424 [MH⁺].

Example 2.481-(3-Cyanophenyl)-N-(3,4-dihydro-2H-pyran-2-ylmethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 350 [MH⁺].

Example 2.491-(3-Cyanophenyl)-6-methyl-N-(4-methylbenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 358 [MH⁺].

Example 2.501-(3-Cyanophenyl)-6-methyl-N-(1-naphthylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 394 [MH⁺].

Example 2.511-(3-Cyanophenyl)-N-(2-ethoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 388 [MH⁺].

Example 2.521-(3-Cyanophenyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 422 [MH⁺].

Example 2.531-(3-Cyanophenyl)-6-methyl-N-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 358 [MH⁺].

Example 2.541-(3-Cyanophenyl)-N-(4-fluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 362 [MH⁺].

Example 2.55N-(1,3-Benzodioxol-5-ylmethyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 388 [MH⁺].

Example 2.561-(3-Cyanophenyl)-N-(2.4-dichlorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 412 [MH⁺].

Example 2.571-(3-Cyanophenyl)-6-methyl-N-(2-methylbenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 358 [MH⁺].

Example 2.581-(3-Cyanophenyl)-N-(3.4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 380 [MH⁺].

Example 2.591-(3-Cyanophenyl)-N-(3-dichlorobenzyl)-6-Methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 412 [MH⁺].

Example 2.601-(3-Cyanophenyl)-6-methyl-N-[(5-methyl-2-furyl)methyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 348 [MH⁺].

Example 2.611-(3-Cyanophenyl)-6-methyl-2-oxo-N-1.2,3,4-tetrahydronaphthalen-1-yl-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 384 [MH⁺].

Example 2.621-(3-Cyanophenyl)-N-(2.3-dimethoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 404 [MH⁺].

Example 2.631-(3-Cyanophenyl)-N-(3,5-dimethoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 404 [MH⁺].

Example 2.641-(3-Cyanophenyl)-N-[1-(4-fluorophenyl)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 376 [MH⁺].

Example 2.65N-[1-(4-Chlorophenyl)ethyl]-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 392 MH⁺].

Example 2.66 1-(3-Cyanophenyl)-N-(2.5-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 380 [MH⁺].

Example 2.671-(3-Cyanophenyl)-N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 386 [MH⁺].

Example 2.68 Methyl4-[({[1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl]carbonyl}amino)methyl]benzoate

APCI-MS m/z: 402 [MH⁺].

Example 2.691-(3-Cyanophenyl)-6-methyl-2-oxo-N-(4-phenoxybenzyl)-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 436 [MH⁺].

Example 2.701-(3-Cyanophenyl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 370 [MH⁺].

Example 2.71 1-(3-Cyanophenyl)-6-methyl-2-oxo-N-(thien-3-ymethyl)-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 350 MH⁺].

Example 2.721-(3-Cyanophenyl)-6-methyl-N-[(5-methylisoxazol-3-yl)methyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 349 [MH⁺].

Example 2.731-(3-Cyanophenyl)-N-[(2,5-dimethyl-3-furyl)methyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 362 [MH⁺].

Example 2.741-(3-Cyanophenyl)-N-(3-furylmethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 334 [MH⁺].

Example 2.751-(3-Cyanophenyl)-6-methyl-2-oxo-N-[4-(1H-pyrazol-1-yl)benzyl-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 410 [MH⁺].

Example 2.761-(3-Cyanophenyl)-6-methyl-2-oxo-N-(4-thien-2-ylbenzyl)-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 426 [MH⁺].

Example 2.77N-[4-(Aminosulfonyl)benzyl]-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 423 [MH⁺].

Example 2.78N-[2-(1,3-Benzodioxol-5-yl)ethyl]-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 402 [MH⁺].

Example 2.791-(3-Cyanophenyl)-6-methyl-2-oxo-N-(2-thien-2-ylethyl)-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 364 [MH⁺].

Example 2.801-(3-Cyanophenyl)-N-[2-(2,4-dimethylphenyl)ethyl]-6-methyl-2oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 386 [MH⁺].

Example 2.811-(3-Cyanophenyl)-6-methyl-N-[2-(4-methylphenyl)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 372 [MH⁺].

Example 2.82N-{2-[4-(Aminosulfonyl)phenyl]ethyl}-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 437 [MH⁺].

Example 2.831-(3-Cyanophenyl)-6-methyl-2-oxo-N-[(1S)-1-phenyl]ethyl}-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 358 [MH⁺].

Example 2.84N-(Cyclohexylmethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 393 [MH⁺].

Example 2.85N-(2-Furylmethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 377 [MH⁺].

Example 2.866-Methyl-2-oxo-N-(pyridin-3-ylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 388 [MH⁺].

Example 2.87N-2,3-Dihydro-1H-inden-1-yl-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 413 [MH⁺].

Example 2.88N-(2-Methoxybenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 417 [MH⁺].

Example 2.896-Methyl-2-oxo-N-(tetrahydrofuran-2-ylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 381 [MH⁺].

Example 2.906-Methyl-2-oxo-1-[3-(trifluoromethyl)phenyl-N-(3,4,5-trimethoxybenzyl)-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 477 [MH⁺].

Example 2.91N-(3-Fluorobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 405 [MH⁺].

Example 2.92N-(2,5-Dimethoxybenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 447 [MH⁺].

Example 2.93N-[(1-Ethylpyrrolidin-2-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 408 [MH⁺].

Example 2.94N-(2-Chlorobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 421 [MH⁺].

Example 2.95N-(4-Chlorobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 421 [MH⁺].

Example 2.96N-(3-Chlorobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 421 [MH⁺].

Example 2.976-Methyl-2-oxo-N-(thien-2-ylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 393 [MH⁺].

Example 2.98 N-(Cyclopropylmethyl)-6-methyl-2-oxo-1-[3(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 351 [MH⁺].

Example 2.99N-(3-Methoxybenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 417 MH⁺].

Example 2.1006-Methyl-2-oxo-N-(pyridin-4-ylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 388 [MH⁺].

Example 2.101N-[2-(3,4-Dimethoxyphenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 461 [MH⁺].

Example 2.102N-[2-(4-Methoxyphenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 431 [MH⁺].

Example 2.1036-Methyl-2-oxo-N-(2-phenylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 401 [MH⁺].

Example 2.1046-Methyl-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 408 [MH⁺].

Example 2.105N-[2-(3-Chlorophenyl)ethyl]-6-methyl-2-oxo-1-(3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 435 [MH⁺].

Example 2.1066-Methyl-2-oxo-N-(2-pyridin-2-ylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 402 [MH⁺].

Example 2.107N-[2-(2-Methoxyphenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 431 [MH⁺].

Example 2.108N-[2-(2-Chlorophenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 435 [MH⁺].

Example 2.109N-[2-(3-Methoxyphenyl)ethyl]-6-ethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 431 [MH⁺].

Example 2.110N-[2-(4-Fluorophenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 419 [MH⁺].

Example 2.111N-[2-(2,4-Dichlorophenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 469 [MH⁺].

Example 2.112N-[2-(3-Fluorophenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 419 [MH⁺].

Example 2.113N-[2-(2-Fluorophenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 418 [MH⁺].

Example 2.114N-(2-Cyclohex-1-en-1-ylethyl)-6-methyl-2-oxo1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 405 [MH⁺].

Example 2.115N-[2-(4-Bromophenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 481 [MH⁺].

Example 2.1166-Methyl-2-oxo-N-[(1S)-1-phenylethyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 401 [MH⁺].

Example 2.117N-(3-Bromobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 467 [MH⁺].

Example 2.118N-(4-Bromobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 467 [MH⁺].

Example 2.119N-(2-Bromobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 467 [MH⁺].

Example 2.120N-(3,4-Dihydro-2H-pyran-2-ylmethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 393 [MH⁺].

Example 2.1216-Methyl-N-(4-methylbenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 401 [MH⁺].

Example 2.1226-Methyl-N-(1-naphthylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 437 [MH⁺].

Example 2.123N-(2-Ethoxybenzyl-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 431 [MH⁺].

Example 2.1246-Methyl-N-(3-methylbenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 401 [MH⁺].

Example 2.125N-(4-Fluorobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 405 [MH⁺].

Example 2.126N-(1,3-Benzodioxol-5-ylmethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 431 [MH⁺].

Example 2.127N-(2,4-Dichlorobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 456 [MH⁺].

Example 2.1286-Methyl-N-(2-methylbenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 401 [MH⁺].

Example 2.129N-(3,4-Difluorobenzyl)-6-methyl-2-oxo-1-[3-(trifluorometlyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 423 [MH⁺].

Example 2.130N-(2-Fluorobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 405 [MH⁺].

Example 2.131N-(2-Chloro-4-fluorobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 439 [MH⁺].

Example 2.132N-(3,4-Dichlorobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 456 [MH⁺].

Example 2.1336-Methyl-N-[(5-methyl-2-furyl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 391 [MH⁺].

Example 2.1346-Methyl-2-oxo-N-1,2,3,4-tetrahydronaphthalen-1-yl-1-3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 427 [MH⁺].

Example 2.135N-(2,3-Dimethoxybenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 447 [MH⁺].

Example 2.136N-[1-(4-Chlorophenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 434 [MH⁺].

Example 2.137N-(2,5-Difluorobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 423 [MH⁺].

Example 2.138 Methyl4-{[({6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-yl}carbonyl)amino]methyl}benzoate

APCI-MS m/z: 445 [MH⁺].

Example 2.1396-Methyl-2-oxo-N-(4-phenoxybenzyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 479 [MH⁺].

Example 2.140N-[(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 411 [MH⁺].

Example 2.1416-Methyl-N-[(5-methylisoxazol-3-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 392 [MH⁺].

Example 2.142N-[(2,5-Dimethyl-3-furyl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 405 [MH⁺].

Example 2.143N-(3-Furylmethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 377 [MH⁺].

Example 2.1446-Methyl-2-oxo-N-[4-(1H-pyrazol-1-yl)benzyl]-1-3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 453 [MH⁺].

Example 2.1456-Methyl-2-oxo-N-(4-thien-2-ylbenzyl)-1-3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 469 [MH⁺].

Example 2.146N-[2-(1,3-Benzodioxol-5-yl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 445 [MH⁺].

Example 2.1476-Methyl-2-oxo-N-(2-thien-2-ylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 407 [MH⁺].

Example 2.148N-[2-(4-Tert-butylphenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 457 [MH⁺].

Example 2.1496-Methyl-N-[2-(4-methylphenyl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 415 [MH⁺].

Example 2.150N-{2-[4-(Aminosulfonyl)phenyl]ethyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 480 [MH⁺].

Example 2.1516-Methyl-2-oxo-N-[(1R)-1-phenylethyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 401 [MH⁺].

Example 2.1523-{[4-(2-Methoxyphenyl)piperazin-1-yl]carbonyl}-6-methyl-1-[3-(trifluoromethyl)phenyl]pyridin-2(1H)-one

APCI-MS m/z: 472 [MH⁺].

Example 2.153N-[(4-Cyanocyclohexyl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 418 [MH⁺].

Example 2.1543-{[4-(4(Fluorophenyl)piperazin-1-yl]carbonyl}-6-methyl-1-[3-(trifluoromethyl)phenyl]pyridin-2(1H)-one

APCI-MS m/z: 460 [MH⁺].

Example 2.155N-[2-(4′-Fluoro-1,1′-biphenyl-4-yl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 495 [MH⁺].

Example 2.156N-(2-Hydroxy-1-phenylethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 417 [MH⁺].

Example 2.1576-Methyl-2-oxo-N-[(2R)-2-phenylcyclopropyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 413 [MH⁺].

Example 2.158N-[1-(4-Chlorobenzyl)piperidin-4-yl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 504 [MH⁺].

Example 2.1596-Methyl-N-(2-morpholin-4-ylethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 410 [MH⁺].

Example 2.160N-[2-(4-chlorophenyl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 435 [MH⁺].

Example 2.161N-(2-Hydroxy-2-phenylethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 417 [MH⁺].

Example 2.162N-Cyclopentyl-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 365 [MH⁺].

Example 2.163N-[2-(1H-Imidazol-4-yl)ethyl]-6-methyl-2-oxo-1-1-3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 391 MH⁺].

Example 2.164N-(3,5-Dimethoxybenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 447 [MH⁺].

Example 2.165N-(4-Hydroxycyclohexyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 395 [MH⁺].

Example 2.1666-Methyl-2-oxo-N-(2-pyridin-2-ylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 402 MH⁺].

Example 2.1676-Methyl-2-oxo-N-1H-1.2.4-triazol-3-yl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 364 [MH⁺].

Example 2.168N-[1-(Hydroxymethyl)-2-methylpropyl]-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 383 [MH⁺].

Example 2.1693-{[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]carbonyl}-6-methyl-1-[3-(trifluoromethyl)phenyl]pyridin-2(1H)-one

APCI-MS m/z: 512 [MH⁺].

Example 2.1706-Methyl-2-oxo-N-(pyridin-3-ylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 388 [MH⁺].

Example 2.171N-(2-Methoxyethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 355 [MH⁺].

Example 2.172N-(2-Hydroxypropyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 355 [MH⁺].

Example 2.173 Ethyl4-[({6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-yl}carbonyl)amino]piperidine-1-carboxylate

APCI-MS m/Z: 452 [MH⁺].

Example 2.174N-[3-(1H-Imdazol-1-yl)propyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 405 [MH⁺].

EXAMPLE 3N-(4-Chlorobenzyl)-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamidea) Diethyl [3-ethoxyprop-2-enylidene]malonate

Diethyl malonate (160 g, 1.0 mole) was added dropwise to a stirred,refluxing solution of 1,1,3,3-tetraethoxypropane (330 g, 1.5 mol),acetic anhydride (306 g, 2.0 moles) and zinc chloride (10 g, 0.073 mole)over a period of 30 minutes. The mixture was heated for 1 h, and afterthat a Dean-Stark apparatus was connected and the lower boilingcomponents were distilled off. Additional acetic anhydride (150 ml) wasadded and refluxing was continued for 1 h. The reaction mixture wasdistilled to give the title compound as a yellow oil (182 g, 75%), b.p.139-143° C. at 0.8 mm Hg.

¹H NMR (CDCl₃): δ 7.38 (1H, d, J=12.1 Hz); 7.04 (1H, d, J=12.2 Hz); 6.19(1H, t, J=12.1 Hz); 4.27 (2H, q); 4.21 (2H, q); 3.96 (2H, q); 1.36-1.24(9H, m).

b) Diethyl {3-[(3-methylphenyl)amino]prop-2-enylidene}malonate

Diethyl [3-ethoxyprop-2-enylidene]malonate (9.7 g, 40 mmol) andm-toluidine (4.3 g, 40; mmol) were dissolved in ethanol (150 ml) andstirred at room temperature for three days. The solvents were evaporatedoff. Column chromatography on silica using heptane/ethyl acetate (4:1)as eluent afforded the title compound as an oil, which solidified afterstanding for a couple of days (10 g, 83%).

¹H NMR (CDCl₃): δ 7.65 (1H, d, J=12.4 Hz); 7.39 (2H, brd, J=7.7 Hz);7.19 (1H, t, J=7.7 Hz); 6.85 (1H, d, J=7.7 Hz); 6.75 (1H, s); 6.73 (1Hd, J=6.5 Hz); 6.46 (1H, m, J=12.4, 6.5 Hz); 4.32 (2H, q); 4.25 (2H, q);2.35 (3H, s); 1.36 (3H, t) 1.33 (3H, t).

APCI-MS m/z: 304 [MH⁺].

c) 1-(3-Methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid

Diethyl {3-[(3-methylphenyl)amino]prop-2-enylidene}malonate (10 g, 33mmol) was mixed with 2M sodium hydroxide solution (100 ml) and stirredat room temperature for 30 minutes. The reaction mixture was extracted(washed) with ethyl acetate and the water phases were acidified withhydrochloric acid to pH 3-4. An orange coloured precipitate appeared andwas filtered off, washed with water and dried to afford the titlecompound (7.3 g, 97%).

¹H NMR (CDCl₃): δ 14.08 (1H, s); 8.64 (1H, dd, J=7.2, 2.2 Hz); 7.72 (1H,dd, J=6.7, 2.2 Hz); 7.47 (1H, t, J=7.7 Hz); 737 (1H, d, J=7.7 Hz); 7.23(1H, s); 7.21 (1H, brd); 6.67 (1H, t, J=7.2, 6.7 Hz); 2.47 (3H, s).

APCI-MS m/z: 230 [MH⁺].

d)N-(4-Chlorobenzyl)-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

To a mixture of1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (115 mg,0.5 mmol), HATU (209 mg, 0.55 mmol), HOAT (75 mg, 0.55 mmol) and DIEA(275 μl, 1.6 mmol) in dichloromethane (2.5 ml) was added4-chlorobenzylamine (71 mg, 0.5 mmol) in dichloromethane (1 ml). Thereaction was stirred for 1 h at room temperature. More dichloromethanewas added and the crude product was washed twice with aqueous sodiumhydrogencarbonate, 0.5M aqueous citric acid and water. The solvent wasremoved in vacuo and the residue was purified by column chromatographyon silica using dichloromethane/ethyl acetate (4:1) as eluent to affordthe title compound in almost quantitative yield.

¹HNMR (CDCl₃): δ 10.10 (1H, brt); 8.68 (1H, dd); 7.58 (1H, dd); 7.43(1H, t); 7.33-7.25 (5H, m); 7.20-7.14 (2H, m); 6.53 (1H, t); 4.59 (2H,d); 2.45 (3H, s).

APCI-MS m/z: 353 [MH⁺].

EXAMPLE 4N-(4-Chlorobenzyl)-6′-methyl-2-oxo-2H-1,2′-bipyridine-3-carboxamide a)Diethyl {3-[(6-methylpyridin-2-yl)amino]prop-2-enylidene}malonate

Diethyl [3-ethoxyprop-2-enylidene]malonate (1.7 g, 7 mmol) and2-amino-6-methylpyridine (1.08 g, 10 mmol) were heated (without solvent)at 140° C. for 6 h. The reaction mixture was worked-up as described inExample 3 (b) to afford the title compound.

APCI-MS m/z: 305 [MH⁺].

b) 6′-Methyl-2-oxo-2H-1,2′-bipyridine-3-carboxylic acid

The title compound was prepared from diethyl{3-[(6-methylpyridin-2-yl)amino]prop-2-enylidene]malonate using themethod described in Example 3 (c).

¹H NMR (CDCl₃): δ 14.02 (1H, brs); 8.65 (1H, dd); 8.20 (1H, dd); 7.84(1H, t); 7.68 (1H, d); 7.33 (1H, d); 6.72 (1H, t); 2.64 (3H, s).

APCI-MS m/z: 231 [MH⁺].

c) N-(4-Chlorobenzyl)-6′-methyl-2-oxo-2H-1,2′-bipyridine-3-carboxamide

The title compound was prepared from6′-methyl-2-oxo-2H-1,2′-bipyridine-3-carboxylic acid and4-chlorobenzylamine using the method described in Example 3 (d).

¹H NMR (CDCl₃): δ 10.04 (1H, brt); 8.68 (1H, dd); 7.95 (1H, dd); 7.79(1H, t); 7.55 (2H, d); 7.29 (5H, brd); 6.58 (1H, t); 4.61 (2H, d); 2.62(3H, s).

APCI-MS m/z: 354

The compounds of Examples 4.1 to 4.18 were prepared by a methodanalogous to that described for Example 4.

Example 4.1N-(4-Methoxybenzyl)-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.98 (1H, brt); 8.68 (1H, dd); 7.56 (1H, dd); 7.42(1H, t); 7.32-7.25 (3H, m); 7.18-7.13 (2H, m); 6.84 (2H, d); 6.52 (1H,t); 4.56 (2H, d); 3.79 (3H, s); 2.43 (3H, s).

APCI-MS m/z: 349 [MH⁺].

Example 4.2 Methyl4-[({[1-(3-methylphenyl)-2-oxo-1,2-dihydropyridin-3-yl]carbonyl}amino)methyl]benzoate

¹H NMR (CDCl₃): δ 10.17 (1H, brt); 8.69 (1H, dd); 7.98 (2H, d); 7.59(1H, dd); 7.46-7.40 (3H, m); 7.32 (1H, d); 7.20-7.16 (2H, m); 6.54 (1H,t); 4.69 (2H, d); 3.92 (3H, s); 2.45 (3H, s).

APCI-MS m/z: 377 [MH⁺].

Example 4.34-[({[1-(3-Methylphenyl)-2-oxo-1,2-dihydropyridin-3-yl]carbonyl}amino)methyl]benzoicacid

A suspension of methyl4-[({[1-(3-methylphenyl)-2-oxo-1,2-dihydropyridin-3-yl]carbonyl}amino)methyl]benzoate(120 mg, 0.32 mmol) and 2M sodium hydroxide solution (0.5 ml) inmethanol (20 ml) and water (10 ml) was stirred at 40° C. overnight. Themethanol was evaporated off and the aqueous solution was acidified with1M hydrochloric acid (1 ml). A beige coloured precipitate appeared whichwas filtered off, washed twice with water and dried to afford the titlecompound (110 mg, 95%).

¹H NMR (DMSO-d₆): δ 12.84 (1H, s); 10.05 (1H, t); 8.45 (1H, dd); 7.99(1H, dd); 7.88 (2H d); 7.43-7.38 (3H, m); 7.30 (1H, d); 7.27 (1H, s);7.24 (1H, d); 6.61 (1H, t); 4.57 (2H, d); 2.35 (3H, s).

APCI-MS m/z: 363 [MH⁺].

Example 4.4N-(4-Chlorobenzyl)-1-(2-fluoro-5-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.97 (1H, brt); 8.69 (1H, dd); 7.51 (1H, dd);7.31-7.26 (5H, m); 7.21-7.15 (2H, m); 6.56 (1H, t); 4.59 (2H, brs); 2.40(3H, s).

APCI-MS m/z: 371 [MH⁺].

Example 4.51-(2-Fluoro-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.86 (1H, brt); 8.69 (1H, dd); 7.49 (1H, dd);7.30-7.25 (3H, m); 7.20-7.14 (2H, m); 6.84 (2H, d); 6.54 (1H, t); 4.56(2H, brd); 3.79 (3H, s); 2.39 (3H, s).

APCI-MS m/z: 367 [MH⁺].

Example 4.6N-[4-(Dimethylamino)benzyl]-1-(2-fluoro-5-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.78 (1H, bit); 8.69 (1H, dd); 7.47 (1H, dd); 7.27(1H, dd); 7.22 (2H, d); 7.19-7.13 (2H, m); 6.68 (2H, d); 6.53 (1H, t);4.53 (2H, brd); 2.92 (6H, s); 2.39 (3H, s).

APCI-MS m/z: 380 [MH⁺].

Example 4.7N-[4-(Aminosulfonyl)benzyl]-1-(2-fluoro-5-methylphenyl-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.11 (1H, brt); 8.69 (1H, dd); 7.86 (2H, d); 7.54(1H, dd); 7.48 (2H, d); 7.30 (1H, dd); 7.20 (2H, d); 7.17 (2H, brd);6.58 (1H, t); 4.68 (2H, brd); 2.41 (3H, s).

APCI-MS m/z: 416 [MH⁺].

Example 4.8N-(4-Chlorobenzyl)-4′-methyl-2-oxo-2H-1,2′-bipyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.02 (1H, brt); 8.68 (1H, dd); 8.48 (1H, d); 7.94(1H, dd); 7.58 (1H, s); 7.30-7.28 (4H, m); 7.23 (1H, d); 6.58 (1H, t);4.61 (2H, d); 2.48 (3H, s).

APCI-MS m/z: 354 [MH⁺].

Example 4.9N-(4-Chlorobenzyl)-1-(2,5-dimethylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.11 (1H, brt); 8.69 (1H, dd); 7.47 (1H, dd);7.29-7.20 (6H, m); 7.02 (1H, s); 6.54 (1H, t); 4.59 (2H, m); 2.38 (3H,s); 2.09 (3H, s).

APCI-MS m/z: 367 [MH⁺].

Example 4.101-(2.5-Dimethylphenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.97 (1H, brt); 8.67 (1H, dd); 7.43 (1H, dd);7.27-7.16 (4H, m); 6.99 (1H, s); 6.81 (2×, d); 6.50 (1H, t); 4.53 (2H,m); 3.77 (3H, s); 2.35 (3H, s); 2.07 (3H, s).

APCI-MS m/z: 363 MH⁺].

Example 4.11N-[4-(Dimethylamino)benzyl]-1-(2,5-dimethylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.91 (1H, brt); 8.69 (1H, dd); 7.43 (1H, dd);7.26-7.19 (4H, m); 7.01 (1H, s); 6.68 (2H, d); 6.52 (1H, t); 4.52 (2H,m); 2.92 (6H, s); 237 (3H, s); 2.08 (3H, s).

APCI-MS m/z: 376 [MH⁺].

Example 4.12N-(4-Chlorobenzyl)-1-[2-methyl-5-(trifluoromethyl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.94 (1H, brt); 8.72 (1H, dd); 7.69 (1H, dd); 7.53(1H, d); 7.50 (1H s); 7.46 (1H, dd); 7.28 (4H, s); 6.60 (1H, t); 4.59(2H, m); 2.23 (3H, s).

APCI-MS m/z: 421 [MH⁺].

Example 4.13N-(4-Methoxybenzyl)-1-[2-methyl-5-(trifluoromethyl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.80 (1H, bit); 8.71 (1H dd); 7.65 (1H, dd); 7.50 (1H,d); 7.47 (1H, s); 7.42 (1H, dd); 7.27-7.24 (4H, m); 6.82 (2H, d); 6.56(1H, t); 4.54 (2H, m); 3.76 (3H, s); 2.19 (3H, s).

APCI-MS m/z: 417 [MH⁺].

Example 4.14N-[4-(Dimethylamino)benzyl]-1-[2-methyl-5-(trifluoromethyl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.75 (1H, bit); 8.73 (1H, dd); 7.67 (1H, dd); 7.52(1H, d); 7.49 (1H, s); 7.42 (1H, dd); 7.23 (2H, d); 6.69 (2H, d); 6.57(1×, t); 4.53 (2H, m); 2.92 (6H, s); 2.21 (3H, s).

APCI-MS m/z: 430 [MH⁺].

Example 4.15N-Benzyl-5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 387 [MH⁺].

Example 4.16N-(2-Chlorobenzyl)-5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 421 [MH⁺].

Example 4.175-Methyl-2-oxo-N-(2-phenylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 401 [MH⁺].

Example 4.18N-(4-Chlorophenyl)-5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 407 [MH⁺].

EXAMPLE 56-Ethyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidea)6-Ethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid

The title compound was prepared from ethyl3-oxo-3-{[3-(trifluoromethyl)phenyl]amino}propanoate and1-methoxypent-1-en-3-one using the method described in Example 1 steps(a) and (b).

¹H NMR (CDCl₃): δ 13.75 (1H, brs); 8.59 (1H, d); 7.87 (1H, d); 7.79 (1H,t); 7.55 (1H, s); 7.49 (1H, d); 6.61 (1H, d); 2.37 (2H, q); 1.20 (3H,t).

APCI-MS m/z: 312 [MH⁺].

b)6-Ethyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was prepared from6-ethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid and 4-methylsulfonyl) benzylamine hydrochloride using the methoddescribed in Example 3 (d).

¹H NMR (CDCl₃): δ 10.00 (1H brt); 8.64 (1H, d); 7.88 (2H, d); 7.82 (1H,d); 7.75 (1H, t); 7.53 (2H, d); 7.52 (1H, s); 7.45 (1H, d); 651 (1H, d);4.68 (2H, m); 3.02 (3H, s); 2.31 (2H, q); 1.17 (3H, t).

APCI-MS m/z: 479 [MH⁺].

The compounds of Examples 5.1 and 5.2 were prepared by a methodanalogous to that described for Example 5.

Example 5.1N-[4-(Methylsulfonyl)benzyl]-2-oxo-6-propyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.00 (1H, brt); 8.62 (1H, d); 7.88 (2H, d); 7.83 (1H,d); 7.75 (1H, t); 7.53 (2H, d); 7.52 (1H, s); 7.45 (1H, d); 6.49 (1H,d); 4.68 (2H, m); 3.02 (3H, s); 2.26 (2H, t); 1.55 (2H, sxt); 0.87 (3H,t).

APCI-MS m/z: 493 [MH⁺].

Example 5.26-Butyl-N-[44-methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.00 (1H, brt); 8.62 (1H, d); 7.88 (211, d); 7.83(1H, d); 7.75 (1H, t); 7.54 (2H, d); 7.52 (1H, s); 7.45 (1H, d); 6.49(1H, d); 4.68 (2H, m); 3.03 (3H, s); 2.29 (2H, t); 1.49 (2H, qv); 1.24(2H, sxt); 0.80 (3H, t).

APCI-MS m/z: 507 [MH⁺].

EXAMPLE 66-(Methoxymethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidea)6-(Bromomethyl)-2-oxo-1-[3{trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid

The title compound was prepared by refluxing6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid (297 mg, 1 mmol),N-bromosuccinimide (240 mg, 1.3 mmol) and2,2′-azobis-2-methylpropionitrile (AIBN) (15 mg) in carbontetrachloride/chloroform (2:1, 5 ml) overnight. The solvent wasevaporated to give the title compound.

APCI-MS m/z: 376/378 [MH⁺].

b)6-(Methoxymethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid

The title compound was prepared by heating crude6(bromomethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid with an excess of sodium methoxide in methanol at 40° C. for 15minutes. The organic solvents were removed, water was added and thereaction mixture was washed with ethyl acetate. The water phases wereacidified with hydrochloric acid to pH 3-4. A yellowish precipitateappeared which was filtered off, washed (water and water/methanol, 1:1)and dried to give the title compound.

¹H NMR (CDCl₃): δ 13.66 (1H, brs); 8.63 (1H, d); 7.87 (1H, d); 7.77 (1H,t); 7.58 (1H, s); 7.50 (1H, d); 6.84 (1H, d); 3.96 (2H, d); 3.27 (3H,s).

APCI-MS m/z: 328 [MH⁺].

c)6-(Methoxymethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was prepared from6-(methoxymethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid and 4-(methylsulfonyl) benzylamine hydrochloride using the methoddescribed in Example 3 (d).

¹H NMR (CDCl₃): δ 9.98 (1H, brt); 8.67 (1H, d); 7.87 (2×, d); 7.82 (1H,d); 7.73 (1H, t); 7.53 (3H, m); 7.47 (1×, d); 6.72 (1H, d); 4.67 (2H,m); 3.92 (2H, d); 3.23 (3H, s); 3.01 (3H, s).

APCI-MS m/z: 495 [MH⁺].

EXAMPLE 76-(Hydroxymethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidea)6-(Hydroxymethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid

The title compound was prepared by heating6-(bromomethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid and dilute sodium hydroxide in methanol for a few minutes. Thereaction mixture was washed with ethyl acetate. The water phases wereacidified with hydrochloric acid. A precipitate appeared which wasrecrystallised several times from ethyl acetate/methanol to give thetitle compound.

¹H NMR (DMSO-d₆): δ 13.99 (1H, brs); 8.53 (1H, d); 8.00 (1H, s); 7.94(1H, d); 7.83 (1H, t); 7.81 (1H, d); 6.94 (1H, d); 5.85 (1H, t); 3.99(2H, d).

APCI-MS m/z: 314 [MH⁺].

b)6-(Hdroxymethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was prepared from6-(hydroxymethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid and 4-(methylsulfonyl) benzylamine hydrochloride using the methoddescribed in Example 3 (d).

¹H NMR (DMSO-d₆): δ 9.92 (1H, brt); 8.49 (1H, d); 7.92-7.81 (4H, m);7.78 (1, t); 7.71 (1H, d); 7.53 (2H, d); 6.78 (1H, d); 5.71 (1H, t);4.57 (2H, brd); 3.95 (2H, brd); 3.16 (3H, s).

APCI-MS m/z: 481 [MH⁺].

EXAMPLE 8N-[4-(Aminosulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamidea)2,4-Dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

3-(Trifluoromethyl)phenyl isocyanate (3.52 g, 22 mmol) was added quicklyto a vigorously stirred ice-cooled solution of aqueous ammonia (10 ml,33%) in acetonitrile (40 ml). The mixture was heated at 40° C. for 10minutes and then the solvent was evaporated. The resulting urea wasredissolved in dry ethanol (15 ml) and diethyl ethoxymethylene-malonate(5 ml, 24.7 mmol) and finally sodium ethoxide solution (50 mmol inethanol) was added, and the mixture was refluxed for 2 h. Water (10 ml)was added and the mixture was allowed to cool, then washed with ethylacetate, acidified to pH-3 with conc. hydrochloric acid and extractedwith ethyl acetate. The organic extracts were dried and evaporated togive a solid material. Recrystallisation from heptane/ethyl acetateafforded the title compound (0.5 g, 7%).

¹H NMR (CDCl₃): δ 12.41 (1H, brd, J=6.4 Hz); 8.15 (1H, d, J=6.4 Hz);7.46 (1H, d, J=7.6 Hz); 7.40 (1H, t, J=7.6 Hz); 7.30 (brs, 1H); 7.22(1H, d, J=7.6 Hz).

APCI-MS m/z: 300 [MH⁺].

b)N-[4-(Aminosulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

The title compound was prepared from2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid and N-[4-(aminosulfonyl)-benzylamine hydrochloride using the methoddescribed in Example 1 (d).

¹H NMR (DMSO-d₆): δ 12.21 (1H, brd); 9.11 (1×1, t); 8.29 (1H, s); 7.81(2H, d); 7.77-7.70 (3H, m); 7.65 (1 d); 7.44 (1H d); 7.28 (2H, s); 4.46(2H, d).

The compounds of Examples 8.1 to 8.8 were prepared using the generalmethod described for Example 8.

Example 8.1N-[4(Dimethylamino)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamidetrifluoroacetate

¹H NMR (CD₃CN): δ 9.73 (1H, brd); 8.96 (1H, brt); 8.35 (1H, d); 7.79(1H, d); 7.72 (1H, t); 7.63 (1H, s); 755 (1H, d); 736 (2H, d); 7.23 (2H,d); 4.49 (2H, d); 3.04 (6H, s).

Example 8.2N-(4-Chlorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

¹H NMR (CD₃CN): δ 9.65 (1H, brd); 8.96 (1H, brt); 8.39 (1H, d); 7.80(1H, d); 7.72 (1×, t); 7.63 (1H, s), 756 (1H, d); 7.33 (2H, d); 7.25(2H, d); 4.49 (2H, d).

Example 8.3N-(2,3-Dihydro-1-benzofuran-5-ylmethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

¹H NMR (CDCl₃): δ 8.53 (1H, d); 7.76 (1H, m); 7.67 (1H, m); 7.53 (1H,m); 7.44 (1H, m), 7.13 (1H, m); 7.04 (1H, m); 6.68 (1H, d); 5.28 (2H,d); 4.57 (2H, t); 3.19 (2H, t).

APCI-MS m/z: 432 [MH⁺].

Example 8.4N-[4-(Methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

¹H NMR (CDCl₃): δ 9.05 (1H, m); 8.52 (1H, d); 8.40 (1H, m); 7.88 (2H,d); 7.75 (1H, d); 7.66 (1H, t); 7.53 (1H, m); 7.49 (2H, d); 7.44 (1H,d); 4.65 (2H, d); 3.01 (3H, s).

APCI-MS m/z: 468 [MH⁺].

Example 8.5N-(4-Bromobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

¹H NMR (CDCl₃): δ 8.90 (1H, m); 8.50 (1H, d); 8.32 (1H, m); 7.74 (1H,d); 7.65 (1H, m); 7.52 (1H, m); 7.42 (3H, m); 7.16 (2H, d); 4.50 (2H,d).

APCI-MS m/z: 467 [MH⁺].

Example 8.6N-(4-Methoxybenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

¹H NMR (CDCl₃): δ 8.86 (1H, m); 8.62-8.53 (2H, m); 7.77 (1H, m); 7.69(1H, m); 7.55 (1H, m), 7.47 (1H, m), 7.24 (2H, m); 6.86 (1H, m); 4.52(2H, d); 3.80 (3H, s).

APCI-MS m/z: 420 [MH⁺].

Example 8.7N-(1,3-Benzodioxol-5-ylmethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

¹H NMR (CDCl₃): δ 8.93 (1H, m); 8.71 (1H, m); 8.54 (1H, t); 7.76 (1H,d); 7.68 (1H, t); 7.54 (1H, m); 7.46 (1H, d); 7.27 (1H, s); 6.85 (1H,d); 6.76 (1H, d); 5.95 (2H, d); 4.56 (1H, d); 4.48 (1H, d).

APCI-MS m/z: 434 [MH⁺].

Example 8.8N-(3-Chlorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

¹H NMR (CDCl₃): δ 10.07 (1H, d); 9.11 (1H, t); 8.54 (1H, d); 7.78 (1H,d); 7.69 (1H, t); 7.55 (1H, m); 7.47 (1H, d); 7.29 (1H, m); 7.26 (2H,m); 7.19 (1H, m); 4.58 (2H, d).

APCI-MS m/z: 424 [MH⁺].

EXAMPLE 91-Butyl-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamidea) N-Butyl-N′-[3-(trifluoromethyl)phenyl]urea

1-Isocyanato-3-(trifluoromethyl)benzene (0.74 ml, 5.34 mmol) was addedto an ice cooled solution of n-butylamine (1.06 ml, 10.68 mmol) inacetonitrile (10 ml). The mixture was stirred for 10 minutes and thenthe solvent was evaporated to give the title compound as a white solid(1.37 g, 99%).

APCI-MS m/z: 261 [MH⁺].

b) Ethyl1-butyl-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

To a solution of N-butyl-N′-[3-(trifluoromethyl)phenyl]urea (1.37 g,5.26 mmol) and diethyl (ethoxymethylene)malonate (2.13 ml, 10.68 mmol)in NMP (6 ml) at 100° C. was added potassium tert-butoxide (0.10 g, 0.89mmol) and the mixture was stirred for 1 h. Ethyl acetate was added andthe mixture was washed with 1M hydrochloric acid, brine and water. Thesolvent was evaporated and the resulting oil was purified by HPLC togive the title compound (667 mg, 33%).

¹HNMR (CDCl₃): δ8.33 (1H, s); 7.70 (1H, d); 7.62 (1H, t); 751 (1H, s);7.41 (1H, d); 4.35 (2H, q); 3.89 (2H, t); 1.81-1.74 (2H, m); 1.45-1.33(5H, m); 0.99 (3H, t).

APCI-MS m/z: 385 [MH⁺].

c)1-Butyl-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

A solution of ethyl1-butyl-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(101 mg, 0.26 mmol) and 0.5M sodium hydroxide solution (700 μl, 0.35mmol) in THF was stirred for 2 h. Water was added and the mixture waswashed with ethyl acetate. Acidification of the aqueous phase,extraction with ethyl acetate and removal of the solvent yielded thetitle compound (65 mg, 70%).

¹H NMR (CDCl₃): δ 8.57 (1H, s); 7.79 (1H, d); 7.70 (1H, t); 7.55 (1H,s); 7.46 (1H, d); 3.96 (2H, t); 1.85-1.75 (2H, m); 1.50-1.37 (2H, m);1.00 (3H, t).

APCI-MS m/z: 357 [MH⁺].

d)1-Butyl-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

A solution of 4-methylsulphonylbenzylamine hydrochloride (30 mg, 0.14mmol) and DIEA (24 μl, 0.14 mmol) in dichloromethane (1 ml) was added toa stirred mixture of1-butyl-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyridine-5-carboxylicacid (44 mg, 0.12 mmol), HATU (52 mg, 0.14 mmol), HOAT (19 mg, 0.14mmol) and DIEA (63 μl, 0.37 mmol) in dichloromethane (1 ml). Theresulting mixture was stirred for 2 h. The solvent was evaporated andthe product was purified by HPLC and by flash chromatography to give thetitle compound (22 mg, 35%).

¹H NMR (CDCl₃): δ 9.14 (1H, t); 8.55 (1H, s); 7.89 (2H, d); 7.75 (1H,d); 7.67 (1H, t); 7.53 (1H, s); 7.50 (2H, d); 7.44 (1H, d); 4.66 (2H,d); 3.93 (2H, t); 3.03 (3H, s); 1.83-1.75 (2H, m); 1.47-1.38 (2H, m);0.99 (3H, t).

APCI-MS m/z: 524 [MH⁺].

The compounds of Examples 9.1 to 9.4 were prepared using the generalmethod described for Example 9:

Example 9.11-(2-Methoxyethyl)-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

¹H NMR (CDCl₃): δ 9.13 (1H, t); 8.61 (1H, s); 7.90 (2H, d); 7.75 (1H,d); 7.67 (1H, t); 7.54 (1H, s); 7.51 (2H, d); 7.45 (1H, d); 4.66 (2H,d); 4.12 (2H, t); 3.68 (2H, t); 3.40 (3H, s); 3.03 (3H, s).

APCI-MS m/z: 526 [MH⁺].

Example 9.21-Methyl-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

¹H NMR (CDCl₃): δ 9.10 (1H, t); 8.57 (1H, s); 7.90 (2H d); 7.76 (1H, d);7.67 (1H, t); 7.52 (1H, s); 7.50 (2H, d); 7.43 (1H, d); 4.66 (2H, d);3.61 (3H, s); 3.03 (3H, s).

APCI-MS m/z: 482 [MH⁺].

Example 9.31-Ethyl-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

¹H NMR (CDCl₃): δ 9.13 (1H, t); 8.58 (1H, s); 7.90 (2H, d); 7.75 (1H,d); 7.67 (1H, t); 7.53 (1H, s); 7.50 (2H, d); 7.44 (1H, d); 4.66 (2H,d); 4.01 (2H, q); 3.03 (3H, s); 1.45 (3H, t).

APCI-MS m/z: 496 [MH⁺].

Example 9.4N-(4-Chlorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

¹H NMR (CDCl₃): δ 8.99 (1H, t); 8.60 (1H, s); 7.74 (1H, d); 7.66 (1H,t); 7.53 (1H, s); 7.44 (1H, d); 7.30-7.22 (4H, m); 4.54 (2H, d); 4.11(2H, t); 3.67 (2H, t); 3.40 (3H, s).

APCI-MS m/z: 482 [MH⁺].

EXAMPLE 105-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

N-Iodosuccinimide (9.7 mg, 0.043 mmol) was added to a stirred solutionof6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(20 mg, 0.043 mmol) in trifluoromethanesulfonic acid (0.5 ml). Themixture was stirred for 10 minutes. Dichloromethane (10 ml) was addedand the organic phase was washed with aqueous sodium hydrogencarbonate,aqueous sodium thiosulfate and water. The extracts were dried andevaporated to give the title compound (100%).

¹H NMR (CDCl₃): δ 9.81 (1H, brt); 8.86 (1H, s); 7.88 (2H, d); 7.82-7.69(3H, m); 7.48 (2H, d); 7.40 (1H, d); 4.65 (2H, m); 3.01 (3H, s); 2.28(3H, s).

The following Intermediates were prepared using the procedure describedin Example 9(c):

1-(2-Methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

APCI-MS m/z: 359 [MH ⁺].

3-(3-Chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

APCI-MS m/z: 325 [MH⁺].

1-Butyl-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

¹H NMR (DMSO-d₆): δ 12.09 (1H, br s); 8.79 (1H, s); 7.39 (1H, t); 7.01(1H, dd); 9.91 (1H, t); 6.85(1H, d); 3.89 (2H, t); 3.74 (3H, s); 1.61(2H, pentet); 1.30 (2]hextet); 0.89 (3H, t).

1-Butyl-3-(3-(trifluoromethyl)phenyl2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

¹H NMR (DMSO-d₆): δ 12.55 (1H, br s); 8.76 (1H, s); 7.84-7.60 (4H, m);3.89 (2H, t); 1.63 (2H, pentet); 1.30 (2H, hextet); 0.89 (3H, t).

1-Butyl-3-(3-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

APCI-MS m/z 323 [MH⁺].

1-Butyl-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

¹H NMR (DMSO-d₆): δ 12.30 (1H, br s); 8.74 (1H, s); 7.94-7.85 (2H, m);7.75-7.69 (2H, m); 3.89 (2×, t); 1.63 (2H, pentet); 1.30 (2H, hextet);0.89 (3H t).

EXAMPLE 11N-(4-Chlorobenzyl)-1-(2-methoxyethyl-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

1-(2-Methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (0.016 mmol, 0.2M in NMP) was added to PS-Carbodiimide resin (60mg), HOBT (0.032 mmol, 0.3M in NMP) and NMP (200 μl). The mixture wasstirred for 15 minutes and 4-chlorobenzylamine (0.019 mmol, 0.3M in NMP)was added. After shaking overnight the excess HOBT was scavenged usingPS-Trisamine resin (45 mg), shaking for 2 h before the resin reagentswere filtered off. The title compound was obtained after purificationusing preparative HPLC.

APCI-MS m/z: 482.4 [MH⁺].

Examples 11.1 to 11.13 were prepared from1-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid and the appropriate amine using the general procedure described inExample 11:

Example 11.1N-(4-Methoxybenzyl)-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 478.5 [MH⁺].

Example 11.2 1-(2-Methoxyethyl)-2,4-dioxo-N-(pyridin4-ylmethyl)-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 449.4 [MH⁺].

Example 11.3N-[2-(3,4-Dimethoxyphenyl)ethyl]-1-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 522.5[MH⁺].

Example 11.41-(2-Methoxyethyl)-N-[2-(3-methoxyphenyl)ethyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 492.5 [MH⁺].

Example 11.51-(2-Methoxyethyl)-N-(4-methylbenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 462.5 [MH⁺].

Example 11.61-(2-Methoxyethyl)-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 526.5 [MH⁺].

Example 11.7N-(4-Fluorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 466.4 [MH⁺].

Example 11.8N-(1,3-Benzodioxol-5-ylmethyl)-1-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 492.5 [MH³⁰].

Example 11.9N-(2-Chloro-4-fluorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 500.4 [MH⁺].

Example 11.10N-(3,4-Dichlorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 516.4, 518.4 [MH⁺].

Example 11.11 Methyl4-{[({1-(2-methoxyethyl)2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-5-yl}carbonyl)amino]methyl}benzoate

APCI-MS m/z: 506.5 [MH⁺].

Example 11.121-(2-Methoxyethyl)-N-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 453.4 [MH⁺].

Example 11.131-(2-Methoxyethyl)-2,4-dioxo-N-[4-(1H-pyrazol-1-yl)benzyl]-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 514.5 [MH⁺].

Examples 11.14 to 11.29 were prepared from3-(3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid and the appropriate amine using the general procedure described inExample 11:

Example 11.14N-(4-Chlorobenzyl)-3-(3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 448.4, 450.4 [MH⁺].

Example 11.153-(3-Chlorophenyl)-N-(4-methoxybenzyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 444.4 [MH⁺].

Example 11.163-(3-Chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-N-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 415.4 [MH⁺].

Example 11.173-3-Chlorophenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 488.5 [MH⁺].

Example 11.183-(3-Chlorophenyl)-1-(2-methoxyethyl)-N-[2-(3-methoxyphenyl)ethyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 458.5 [MH⁺].

Example 11.19N-(3-Bromobenzyl)-3-(3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 492.4, 494.3 [MH⁺].

Example 11.203-(3-Chlorophenyl)-1-(2-methoxyethyl)-N-(4-methylbenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 428.4 [MH ⁺.

Example 11.213(3-Chlorophenyl)-1-(2-methoxyethyl)-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 492.4 [MH⁺].

Example 11.223-(3-Chlorophenyl)-N-(4-fluorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 432.4 [MH⁺].

Example 11.23N-(1,3-Benzodioxol-5-ylmethyl)-3-(3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 458.4 [H⁺].

Example 11.243-(3-Chlorophenyl)-N-(3.4-difluorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 450.3 [MH⁺].

Example 11.25N-(2-Chloro-4-fluorobenzyl)-3-(3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 466.4, 468.4 [MH⁺].

Example 11.263-(3-Chlorophenyl)-N-(3,4-dichlorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 482.3, 484.3 [MH⁺].

Example 11.27 Methyl4-[({[3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]carbonyl}amino)methyl]benzoate

APCI-MS m/z: 472.4 [MH⁺].

Example 11.283-(3-Chlorophenyl)-1-(2-methoxyethyl)-N-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 419.4 [MH⁺].

Example 11.293-(3-Chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-N-[4-(1H-pyrazol-1-yl)benzyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 480.5 [MH⁺].

Examples 11.30 to 11.38 were prepared from1-butyl-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid and the appropriate amine using the general procedure described inExample 11:

Example 11.30 1-Butyl-N-(4-chlorobenzyl)-3-(3-methoxyhenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 442.4 [MH⁺].

Example 11.311-Butyl-3-(3-methoxyphenyl)-N-[2-(3-methoxyphenyl)ethyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 452.3 [MH⁺].

Example 11.32N-(3-Bromobenzyl)-1-butyl-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 486.4, 488.4 [MH⁺].

Example 11.331-Butyl-N-(4-fluorobenzyl)-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 426.3 [MH⁺].

Example 11.34 N-(1,3-Benzodioxol-5-ylmethyl)-1-butyl-3-(3-methoxyphenyl2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 452.4 [MH⁺].

Example 11.351-Butyl-N-(2,4-dichlorobenzyl)-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 476.4, 478.4 [H⁺].

Example 11.361-Butyl-N-(3,4-difluorobenzyl)-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 444.3 [MH⁺].

Example 11.371-Butyl-N-(2-chloro-4-fluorobenzyl)-3-(3-methoxyphenyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 460.3 [MH⁺].

Example 11.381-Butyl-N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 450.5 [MH⁺].

Examples 11.39 to 11.58 were prepared from1-butyl-3-(3-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid and the appropriate amine using the general procedure described inExample 11:

Example 11.391-Butyl-N-(4-chlorobenzyl)-3-(3-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 446.4, 448.4 [MH⁺].

Example 11.401-Butyl-3-(3-chlorophenyl)-N-(4-methoxybenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 442.4 MH⁺].

Example 11.41 1-Butyl-3-(3-chlorophenyl)-2,4-dioxo-N-(pyridin-4-ylmethyl1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z. 413.3 [MH⁺].

Example 11.421-Butyl-3-(3-chlorophenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 486.4 [MH⁺].

Example 11.431-Butyl-3-(3-chlorophenyl)-N-[2-(3-methoxyphenyl)ethyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 456.4 [MH⁺].

Example 11.44N-(3-Bromobenzyl)-1-butyl-3-(3-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 490.3, 492.3 [MH⁺].

Example 11.45N-(4-Bromobenzyl)-1-butyl-3-(3-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 490.3, 492.3 [MH⁺].

Example 11.461-Butyl-3-(3-chlorophenyl)-N-(4-methylbenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 426.4 [MH⁺].

Example 11.471-Butyl-3-(3-chlorophenyl)-N-[4-(methylsulfonyl)benzyl]-2.4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 490.4 [MH⁺].

Example 11.481-Butyl-3-(3-chlorophenyl)-N-(4-fluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 430.4 [MH⁺].

Example 11.49N-(1,3-Benzodioxol-5-ylmethyl)-1-butyl-3-(3-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 456.4 [MH⁺].

Example 11.501-Butyl-3-(3-chlorophenyl)-N-(2,4-dichlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 480.3, 482.3 [MH⁺].

Example 11.511-Butyl-3-(3-chlorophenyl)-N-(3,4-difluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 448.4 [MH⁺].

Example 11.521-Butyl-N-(2-chloro-4-fluorobenzyl)-3-(3-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 464.4, 466.4 [MH⁺].

Example 11.531-Butyl-3-(3-chlorophenyl)-N-(3,4-dichlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 480.3, 482.4 [MH⁺].

Example 11.541-Butyl-3-(3-chlorophenyl)-N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 452.4 [MH⁺].

Example 11.551-Butyl-3-(3-chlorophenyl)-N-[(4-cyanocyclohexyl)methyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 443.3 [MH⁺].

Example 11.561-Butyl-3-(3-chlorophenyl)-N-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 417.3 [MH⁺].

Example 11.571-Butyl-3-(3-chlorophenyl)-2,4-dioxo-N-[4-(1H-pyrazol-1-y)benzyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 478.4 [MH⁺].

Example 11.581-Butyl-3-(3-chlorophenyl)-2,4-dioxo-N-[3-(2-oxopyrrolidin-1-yl)propyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 447.3 [MH⁺].

Examples 11.59 to 11.77 were prepared from1-butyl-3-(3-cyanophenyl)-2,4-dioxo1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and the appropriate amineusing the general procedure described in Example 11:

Example 11.591-Butyl-N-(4-chlorobenzyl)-3-(3-cyanophenyl)-2,4-dioxo-1.2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 437.4 [MH⁺].

Example 11.601-Butyl-3-(3-cyanophenyl)-N-(4-methoxybenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 433.5 [MH⁺].

Example 11.611-Butyl-3-(3-cyanophenyl)-2,4-dioxo-N-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 404.3 [MH⁺].

Example 11.621-Butyl-3-(3-cyanophenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 477.4 [MH³⁰].

Example 11.631-Butyl-3-(3-cyanophenyl)-N-[2-(3-methoxyphenyl)ethyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 447.3 [MH⁺].

Example 11.64N-(3-Bromobenzyl)-1-butyl-3-(3-cyanophenyl)-2,4-dioxo-1.2.3.4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 481.4, 483.4 [MH⁺].

Example 11.65N-(4-Bromobenzyl)-1-butyl-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 481.4, 483.4 [MH⁺].

Example 11.661-Butyl-3-(3-cyanophenyl)-N-(4-methylbenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 417.4 [MH⁺].

Example 11.671-Butyl-3-(3-cyanophenyl)-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 481.4 [MH⁺].

Example 11.681-Butyl-3-(3-cyanophenyl)-N-(4-fluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 421.3 [MH⁺].

Example 11.69N-(1,3-Benzodioxol-5-ylmethyl)-1-butyl-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 447.4 [MH⁺].

Example 11.701-Butyl-3-(3-cyanophenyl)-N-(2.4-dichlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 471.4, 473.4 [MH⁺].

Example 11.711-Butyl-3-(3-cyanophenyl)-N-(3-difluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 439.4 [MH⁺].

Example 11.721-Butyl-N-(2-chloro-4-fluorobenzyl)-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 455.4 [MH⁺].

Example 11.731-Butyl-3-(3-cyanophenyl)-N-(3,4-dichlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z. 471.4, 473.5 [MH⁺].

Example 11.741-Butyl-N-[(4-cyanocyclohexyl)methyl]-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 434.5 [MH⁺].

Example 11.751-Butyl-3-(3-cyanophenyl)-N-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 408.4 [MH⁺].

Example 11.761-Butyl-3-(3-cyanophenyl-2,4-dioxo-N-[4-(1H-pyrazol-1-yl)benzyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 469.5 [MH⁺].

Example 11.771-Butyl-3-(3-cyanophenyl)-2,4-dioxo-N-[3-(2-oxopyrrolidin-1-yl)propyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 438.4 [MH⁺].

Examples 11.78 to 11.97 were prepared from1-butyl-3-(3-(trifluoromethyl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid and the appropriate amine using the general procedure described inExample 11:

Example 11.781-Butyl-N-(4-chlorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 480.4, 482.4 [MH⁺].

Example 11.791-Butyl-N-(4-methoxybenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 476.5 [MH⁺].

Example 11.801-Butyl-2,4-dioxo-N-(pyridin-4-ylmethyl)-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 447.4 [MH⁺].

Example 11.811-Butyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 520.4 [MH⁺].

Example 11.821-Butyl-N-[2-(3-methoxyphenyl)ethyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 490.4 [MH⁺].

Example 11.83N-(3-Bromobenzyl)-1-butyl-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 524.4, 526.5[MH⁺].

Example 11.84 N-(4-Bromobenzyl)-1-butyl-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 524.4, 526.5 [MH⁺].

Example 11.851-Butyl-N-(4-methylbenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyridine-5-carboxamide

APCI-MS m/z: 460.4 [MH⁺].

Example 11.861-Butyl-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 524.5 [MH⁺].

Example 11.871-Butyl-N-(4-fluorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 464.4 [MH⁺].

Example 11.88N-(1,3-Benzodioxol-5-ylmethyl)-1-butyl-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 490.5 [MH⁺].

Example 11.891-Butyl-N-(2,4-dichlorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 514.4, 516.4 [MH⁺].

Example 11.901-Butyl-N-(3,4-difluorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 482.5 [MH⁺].

Example 11.911-Butyl-N-(2-chloro-4-fluorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl]phenyl}-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 498.4, 500.4 [MH⁺].

Example 11.921-Butyl-N-(3,4-dichlorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 514.4, 516.4 [MH⁺].

Example 11.931-Butyl-N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 486.5 [MH⁺].

Example 11.941-Butyl-N-[(4-cyanocyclohexyl)methyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 477.5 [MH⁺].

Example 11.951-Butyl-N-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 451.3 [MH⁺].

Example 11.96 1-Butyl-2,4-dioxo-N-[4(1H-pyrazol-1-yl)benzyl]-3-[3-(trifluoromethyl)phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 512.5 [MH⁺].

Example 11.971-Butyl-2,4-dioxo-N-[3-(2-oxopyrrolidin-1-yl)propyl]-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

APCI-MS m/z: 481.4 [MH⁺].

Example 126-(Chloromethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was prepared by heating6-(hydroxymethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(48 mg, 0.1 mmol) and an excess of thionyl chloride (1 ml) in CH₂Cl₂ (10ml) for 1 h. Removal of the solvents afforded the product (50 mg, 100%)as a white solid after trituration from diethyl ether.

¹H-NMR (DMSO-d₆): δ 9.93 (1H, brt); 8.67 (1H, d); 7.88 (2H, d); 7.86(1H, d); 7.76 (1H, t); 7.61 (1H, s); 754 (1H, d); 7.52 (2H, d); 6.75(1H, d); 4.68 (2H, m); 4.12 (2H, s); 3.02 (3H, s).

APCI-MS m/z: 499 [MH⁺].

EXAMPLE 13N-[4-(Methylsulfonyl)benzyl]-6-[(methylthio)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was prepared by stirring6-(chloromethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(40 mg, 0.08 mmol) with an excess of sodium methylthiolate (28 mg, 0.4mmol) in NMP (10 ml) at room temperature overnight. Water was added andthe reaction mixture was extracted with EtOAc. The crude product waspurified by column chromatography on silica using EtOAc/heptane (4:1) aseluent to afford 15 mg (37%) of the title compound.

¹H-NMR (CDCl₃): δ 9.97 (1H, brt); 8.63 (1H, d); 7.88 (2H, d); 7.81 (1H,d); 7.73 (1H, t); 7.62 (1H, s); 7.53 (3H, m); 6.51 (1H, d); 4.67 (2H,m); 3.26 (2H, d); 3.02 (3H, s); 2.03 (3H, s).

APCI-MS m/z: 511 [MH⁺].

EXAMPLE 14N-[4-(Methylsulfonyl)benzyl]-6-({[4-(methylsulfonyl)benzyl]amino}methyl)-2-oxo-1-3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was prepared by stirring6-(chloromethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidewith an excess of 4-methylsulfonyl) benzylamine hydrochloride and DIEAin NMP at room temperature overnight. The crude product was purified bypreparative HPLC.

APCI-MS m/z: 648 [MH⁺].

EXAMPLE 15N-[4-(Methylsulfonyl)benzyl]-6-(morpholin-4-ylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was, prepared by stirring6-(chloromethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidewith an excess of morpholine in THF at 50° C. overnight. The crudeproduct was purified by preparative HPLC.

APCI-MS m/z: 550 [MH⁺].

Example 166-(Cyanomethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was prepared by stirring6-(chloromethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidewith an excess of sodium cyanide in THF at 50° C. overnight. The crudeproduct was purified by preparative HPLC.

APCI-MS m/z: 490 [MH⁺].

Example 176-Isopropyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidea)6-Isopropyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid

A mixture of ethyl 3-oxo-3-([3-(trifluoromethyl)phenyl]amino}propanoate(5.5 g, 20 mmol), 1-methoxy-4-methylpent-1-en-3-one (prepared using themethod of S. M. Bromidge et al, Synth. Commun., 23(4), 487494 (1993)(2.7 g, 21 mmol) and sodium methoxide (2 g, 40 mmol) in ethanol (50 ml)was heated to reflux for 5 h and then cooled. Water (50 ml) and 2M NaOHwere added and the mixture stirred at room temperature overnight. Theorganic solvents were removed and the reaction mixture extracted withEtOAc. The aqueous phases were acidified with 0.5M citric acid to pH 34,the precipitate formed was filtered off, washed with water and dried toafford 0.4 g (6%) of the title compound as a brownish powder.

¹H-NMR (CDCl₃): δ 13.74 (1H, s); 8.59 (1H, d); 7.87 (1H, d); 7.78 (1H,t); 7.54 (1H, brs); 7.48 (1H, d); 6.64 (1H, d); 2.54 (1H, m); 1.20 (6H,t).

APCI-MS m/z: 326 [MH⁺].

b)6-Isopropyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropridine-3-carboxamide

To a mixture of6-isopropyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid (98 mg, 0.3 mmol), HATU (126 mg, 0,33 mmol), HOAT (45 mg, 0,33mmol) and DIEA (162 W, 0.95 mmol) in NMP (3 ml) was added4-(methylsulfonyl) benzylamine hydrochloride (69 mg, 0.31 mmol), the pHwas adjusted to approx. pH 8-9 with DIEA.

The mixture was stirred for 1 h at room temperature. EtOAc was added andthe organic phase washed twice with aqueous sodium hydrogen carbonate,0.5M citric acid and water. The solvent was removed in vacuo and theresidue was purified by column chromatography on silica usingCH₂Cl₂/EtOAc (4:1) as eluent to afford the title compound inquantitative yield.

¹H-NMR (CDCl₃): δ 9.99 (1H, brt); 8.65 (1H, d); 7.87 (2H, d); 7.82 (1H,d); 7.74 (111, t); 7.51 (3H, m); 7.44 (1H, d); 654 (1H, d); 4.67 (2H,m); 3.01 (3H, s); 2.49 (1H, m); 1.17 (6H, t).

APCI-MS m/z: 493 [MH⁺].

EXAMPLE 18N-[4-(Ethylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidea) tert-Butyl [4-(methylsulfonyl)benzyl]carbamate

To a solution of [4-(methylsulfonyl)benzyl]amine (600 mg, 2.7 mmol) inTBF (9 ml), di-tert-butyldicarbonate (590 mg, 2.7 mmol) and DEA (926 μl,5.4 mmol) were added and the mixture was stirred overnight. Afterremoval of the solvent the crude product was purified by flashchromatography to give the subtitle compound (650 mg, 84%).

¹H-NMR (CDCJ₃): δ 7.91 (2H, d); 7.49 (2H, d); 5.00 (1H, bs); 4.42 (2H,d); 3.05 (3H, s); 1.48 (9H, s).

APCI-MS m/z: 169.1, 186.1 [MH⁺].

b) tert-Butyl [4-(ethylsulfonyl)benzyl]carbamate

To a solution of tert-butyl [4-methylsulfonyl)benzyl]carbamate (400 mg,1.4 mmol) in THF (5 ml) at −72° C., n-butyl lithium (1750 μl, 2.8 mmol)was added dropwise while maintaining the temperature at −70° C. Afteraddition the temperature was allowed to rise to 40° C. and methyl iodide(105 μl, 1.7 mmol) added. The mixture was stirred for 1 h, an aqueoussolution of NH₄Cl was added and then the mixture was extracted withEtOAc. The organic layer was washed with NH₄Cl solution and evaporated.The crude product was purified by preparative HPLC to give the subtitlecompound (148 mg, 35%).

¹H NMR (CDCl₃): δ 7.88 (2H, d); 7.49 (2H, d); 4.98 (1H, bs); 4.43 (2H,bs); 3.11 (2H, q); 1.48 (9H, s); 1.28 (3H, t).

APCI-MS m/z: 183.2, 200.2 [MH⁺].

c) [4(Ethylsulfonyl)benzyl]amine trifluoroacetate

Tert-butyl [4-(ethylsulfonyl)benzyl]carbamate (148 mg, 0.5 mmol) wasstirred in 10% TFA in CH₂Cl₂ for 3 h The solvent was evaporated leavingthe title compound (191 mg).

APCI-MS m/z: 200.1 [MH⁺].

d)N-[4-(Ethylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was obtained from 4-(ethylsulfonyl)benzylaminetrifluoroacetate and1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid using aprocedure analogous to that described in Example 17.

¹H-NMR (CDCl₃): δ 9.98 (1H, t); 8.59 (1H, d); 7.84-7.81 (3H, m); 7.74(1H, t); 7.52-7.50 (3H, m); 7.45 (1H, d); 6.48 (1H, d); 4.74-4.63 (2H,m); 3.08 (21 q); 2.09 (3H, t); 1.26 (3H, t).

APCI-MS m/z: 479.3 [MH⁺].

EXAMPLE 19N-[3-Chloro-4-(methylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidea) 3-Chloro-4-(methylthio)benzaldehyde

To a stirred solution of 2-chlorothioanisole (1.25 ml, 9.5 mmol) inCH₂Cl₂ at −5° C., titanium(IV) chloride (2076 μl, 18.9 mmol) was addeddropwise over 10 min, while maintaining the temperature below 0° C.After addition the mixture was stirred for 10 min beforeα,α-dichloromethyl methyl ether (0.94 ml, 10.4 mmol) was added dropwisemaintaining the temperature below 0° C. After addition, the mixture wasallowed to reach ambient temperature and poured onto a saturated aqueoussolution of sodium bicarbonate (70 ml). The mixture was filtered througha plug of celite, washing with CH₂Cl₂. The phases were separated and theaqueous phase was extracted with CH₂Cl₂. The combined organic phaseswere washed with brine and the solvent removed in vacuo. The crudeproduct was purified by flash chromatography to yield the subtitleproduct (535 mg, 30%).

¹H-NMR (CDCl₃): δ 9.91 (1H, s); 7.84 (1H, d); 7.75 (1H, dd); 7.27 (1H,d); 2.56 (3H, s).

APCI-MS m/z: 187.1 [MH⁺].

b) [3-Chloro-4-(methylthio)phenyl]methanol

To a solution of 3-chloro-4-(methylthio)benzaidehyde (332 mg, 1.8 mmol)in THF (6 ml) and water (0.6 ml), NaBH4 (269 mg, 7.1 mmol) was added.The mixture was stirred for 2 h. The reaction was quenched with 1Maqueous HCl and EtOAc was added. After separating the phases, theorganic layer was washed with water, dried and evaporated to afford thesubtitle compound (350 mg, 91%).

¹H NMR (CDCl₃): δ 7.39 (1H, d); 7.26 (1H, dd); 7.17 (1H, d); 4.66 (2H,9); 2.49 (3H, s).

APCI-MS m/z: 170.9 [MH⁺].

c) [3-Chloro-4-(methylsulfonyl)phenyl]methanol

[3-Chloro-4-(methylthio)phenyl]methanol (350 mg, 1.9 mmol) was dissolvedin aqueous sodium hydroxide (0.5M, 4.44 ml) and stirred for 20 min,sodium bicarbonate (1.23 g) and acetone (1.5 ml) were added followed byaddition of Oxone® (1.85 g, 3.0 mmol) in EDTA (6.5 ml, 0.4 mM). Afterstirring for 2 h the reaction was quenched by addition of sodiumbisulphite (0.9 g) in water. EtOAc was added and the solution wasacidified with aqueous 2M HCl. Sodium chloride was added to the aqueouswhich was then extracted with EtOAc. The organic layers were combinedand washed with water, brine and dried. Evaporation afforded thesubtitle compound as a white solid (359 mg, 88%).

¹H-NMR (CDCl₃): δ 8.12 (1H, d); 7.60 (1H, d); 7.44 (1H, dd); 4.81 (2H,s); 3.27 (3H, s).

d) 4-(Bromomethyl)-2-chloro-1-(methylsulfonyl)benzene

[3-Chloro-4-(methylsulfonyl)phenyl]methanol (239 mg, 1.1 mmol) was addedto dioxane. The slurry was stirred and heated to 40° C. before additionof PBr₃ (71 μl, 0.8 mmol). The reaction was heated to 100° C. for 1 hand then allowed to cool. Water was added and the mixture extracted withEtOAc. The organic layer was washed with water followed by brine anddried. Evaporation afforded the subtitle compound (310 mg, 100%).

¹H-NMR (CDCl₃): δ 8.14 (1H, d); 7.61 (1H, d); 7.49 (1H, dd); 4.46 (2H,s); 3.28 (3H, s).

e) [3-Chloro-4-(methylsulfonyl)benzyl]amine

4-(Bromomethyl)-2-chloro-1-(methylsulfonyl)benzene (160 mg, 0.56 mmol)was dissolved in methanol (3 ml) and added to an equal mixture ofammonia (28%) and methanol (10 ml). The reaction was stirred at 40° C.for 1 h and evaporated. The crude is product was dissolved in EtOAc andaqueous 6M sulphuric acid. The aqueous phase was separated, adjusted topH 14 using sodium hydroxide and extracted with CH₂Cl₂. The CH₂Cl₂ phasewas dried and evaporated to afford the title compound (65 mg, 53%).

APCI-MS m/z: 219.9 [MH⁺].

f)N-[3-Chloro-4-(methylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was prepared as described in Example 17.

¹H-NMR (CDCl₃): δ 10.03 (1H, t); 8.58 (1H, d); 8.07 (1H, d); 7.82 (1H,d); 7.75 (1H, t); 7.52 (2H, d); 7.45 (1H, d); 7.41 (1H, d); 6.49 (1H,d); 4.69-4.57 (2H, m); 3.23 (3H, s); 2.10 (3H, s).

APCI-MS m/z: 499.0 [MH⁺].

EXAMPLE 206-Methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-cyclopropanesulfonyl-benzylamide a)4-Cyclopropanesulfonyl-benzylamine

1-Cyclopropanesulfonyl-4-methyl-benzene, prepared by the method of W. E.Truce, et al, J. Org. Chem., 1961, 26, 1463-1467, (190 mg, 0.969 mmol),N-bromosuccinimide (190 mg, 1.07 mmol) and benzoyl peroxide (12 mg) incarbon tetrachloride (4 ml) were heated under reflux for 24 h, cooled,filtered and concentrated. The residue in methanol (1 ml) was added inportions during 10 min to a solution of ammonium hydroxide (28%, 2 ml)in methanol (2 ml). After 2 h the solution was partitioned between EtOAc(10 ml) and sulphuric acid (0.4M, 10 ml), the pH of the aqueous layerwas adjusted to 14 using 2M aqueous KOH and then extracted three timeswith dichloromethane. The organic phase was dried and concentrated togive the subtitle compound (83 mg).

¹H-NMR (CDCl₃): δ 7.78 (2H, bd); 7.35 (2H, bd); 2.46 (3H, s); 2.46 (1H,m); 1.34 (2H, m); 1.02 (2H, m).

APCI-MS m/z: 212 [MH⁺].

The corresponding dibenzyl armine (12%) is also present.

b)6-Methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-cyclopropanesulfonyl-benzylamide

The title compound was obtained from 4-cyclopropanesulfonyl-benzylamineand 1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid by amethod analogous to that described in Example 17.

¹H-NMR (CDCl₃): δ 9.93 (1H, brt); 8.38 (1H, d); 7.89 (2H, bd); 7.84-7.80(3H, m); 7.73 (1H, bd); 7.53 (2H, d); 6.26 (1H, d); 4.58 (2H, d); 2.80(1H, m); 2.02 (3H, s); 1.08 (2H, m); 1.01 (2H, m).

APCI-MS m/z: 491.1 [MH⁺].

EXAMPLE 21N-[3-Methoxy-4-(methylysulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidea) [3-Methoxy-4-(methylsulfonyl phenyl]methanol

[3-Methoxy-4-(methylthio)phenyl]methanol, prepared as described byGarcia et al. Supramolecular Chemistry, 1992, 1, 3145, (75 mg, 0.4 mmol)was dissolved in aqueous sodium hydroxide (0.5M, 1.22 ml) and stirredfor 30 min. Further reaction as in Example 19 (c) gave, after trituationwith toluene, the subtitle compound as white crystals (47 mg, 54%).

¹H-NMR (CDCl₃): δ 7.97 (d, J 8.0 Hz, 1H); 7.15 (s, 1H); 7.08 (d, J 8.0Hz, 1H); 4.81 (d, J=5.4 Hz, 2H); 4.04 (s, 3H); 3.32 (s, 3H).

APCI-MS m/z: 217 [MH⁺].

b) 4(Bromomethyl)-2-methoxy-1-(methylsulfonyl)benzene

To a slurry of [3-methoxy-4-(methylsulfonyl)phenyl]methanol (69 mg, 0.32mmol) and toluene at 40° C. was added PBr₃ (30 μl, 0.32 mmol). Thereaction was heated to 100° C. for 1 h, cooled and water added. Thereaction mixture was diluted with EtOAc, washed with water and brine anddried. Evaporation afforded the subtitle compound as a pale yellow oil(62 mg, 69%).

¹H-NMR (CDCl₃): δ 7.97 (d, J 8.0 Hz, 1H); 7.14 (dd, J 8.0, 1.4 Hz, 1H);7.10 (d, J 1.2 Hz, 1H); 4.50 (s, 2H); 4.05 (s, 3H); 3.24 (s, 3H).

APCI-MS m/z: 280 [MH⁺].

c) 3-Methoxy-4-(methylsulfonyl)benzylamine

4(Bromomethyl)-2-methoxy-1-(methylsulfonyl)benzene (62 mg, 0.22 mmol) inmethanol was slowly added to an equal mixture of ammonia (28%) andmethanol. The reaction was stirred at room temperature for 2 h andevaporated. The reaction mixture was partitioned was between EtOAc andaqueous 6M sulphuric acid The aqueous phase was made alkaline withsodium hydroxide and extracted with CH₂Cl₂; The CH₂Cl₂ phase was driedand evaporated to afford the title compound (36 mg, 76%).

APCI-MS m/z: 216 [MH⁺].

d)N-[3-Methoxy-4-(methylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was obtained from 3-methoxy(methylsulfonyl)benzylamine and1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid by amethod analogous to that described in Example 17.

¹H-NMR (CDCl₃): δ 10.03 (s, 1H); 8.60 (d, J 7.5 Hz, 1H); 7.91 (d, J 8.1Hz, 1H); 7.83 (d, J=8.3 Hz, 1H); 7.76 (t, J=7.8 Hz, 1H); 7.54 (d, J 4.7Hz, 1H); 7.46 (d, J 7.2 Hz, 1H); 6.50 (d, J 7.2 Hz, 1H); 7.05 (td, J7.9, 5.3 Hz, 2H); 4.64 (t, J 6.3 Hz, 2H); 3.98 (s, 3H); 3.19 (s, 3H);2.11 (s, 3H).

APCI-MS m/z: 495 [MH⁺].

EXAMPLE 22N-[3-Bromo-4-(methylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidea) 3-Bromo-4 (methylthio)benzaldehyde

To a solution of 3-bromo-4-fluorobenzaldehyde (0.5 g, 2.5 mmol) in NMP(10 ml), potassium carbonate (0.68 g, 4.92 mmol) and sodiummetanethiolate (0.26 g, 3.69 mmol) were added. The mixture was heated to70° C. for 7 h, cooled, and partitioned between EtOAc and water. Theorganic phase was dried, filtered, evaporated and purified by columnchromatography on silica using heptane/EtOAc (4:1) as eluent to affordthe title compound (0.25 g, 44%).

¹H-NMR (CDCl₃): δ 9.89 (1H, s); 8.00 (1H, d); 7.79 (1H, dd); 7.23 (1H,d); 2.54 (3H, s).

APCI-MS m/z: 465.3 [MH⁺].

b) [3-Bromo-4(methylthio)phenyl]methanol

To a solution of 3-bromo-4-(methylthio)benzaldehyde (0.25 g, 1.08 mmol)in methanol (15 ml) was added sodium borohydride (0.2 g, 5.4 nmol). Thesolution was stirred at room temperature for 4 h, water was added, andthe mixture was extracted with CH₂Cl₂. The organic layer was dried,filtered and evaporated to give 0.24 g (95%) of the title compound.

¹H-NMR (CDCl₃): δ 7.55 (1H, d); 7.29 (1H, dd); 7.12 (1H, d); 4.64 (2H,s); 2.48 (3H, s).

c) [3-Bromo-4-(methylsulfonyl)phenyl]methanol

A suspension of sodium hydroxide (2.5 ml, 1.25 mmol) and[3-bromo-4-(methylthio)phenyl]methanol (0.24 g, 1.03 mmol) was stirredat ambient temperature for 20 min, then sodium bicarbonate (0.69 g, 8.2mmol) and acetone (1 ml) were added, followed by a Oxone® solution (1.6g in 6 ml of 0.4 mM EDTA) added over 10 min. The suspension was stirredovernight at room temperature. EtOAc was added and the solution wasacidified with 5M HCl. The organic phase was washed several times withwater and then dried, filtered and evaporated to give the title compound0.19 g (70%).

APCI-MS m/z: 249.1, 251 [MH⁺].

d) 2-Bromo-4-(bromomethyl)-1-(methylsulfonyl)benzene[3-Bromo-4-(methylsulfonyl)phenyl]methanol (0.19 g, 0.72 mmol) was mixedwith toluene (5 ml) and phosphorus tribromide (30 μl, 0.32 mmol) at 40°C., and the mixture was stirred at 100° C. for 20 min. EtOAc (100 ml)was added to the cooled solution and then washed with water. The organicphase was dried, filtered and evaporated to give 0.23 g (97%) of thetitle compound

¹H-NMR (DMSO-d₆): δ 8.06 (1H, d); 8.02 (1H, d); 7.73 (1H, dd); 4.76 (2Hz s); 3.38 (3H, s).

e) [3-Bromo-4-(methylsulfonyl)benzyl]amine

A solution of 2-bromo-4-(bromomethyl)-1-(methylsulfonyl)benzene (230 mg,0.70 mmol) in methanol (3 ml) and THF (1 ml) was added to NH₄OH (7 ml,28%) during 30 min After 4 h the solution was acidified with 0.5M HCl,washed twice with CH₂Cl₂ and then basified to pH 14 with 5M sodiumhydroxide. The water phase was extracted with CH₂Cl₂, and the organiclayer was dried, filtered and evaporated to give 80 mg (43%) of thetitle compound.

¹H-NMR (DMS-d₆): δ 7.99 (1H, d); 7.89 (1H, d); 7.58 (1H, dd); 3.79 (2H,s); 3.31 (3 H, s).

APCI-MS m/z: 264, 266 [MH⁺].

f)N-[3-Bromo-4-(methylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was obtained from[3-bromo-4-(methylsulfonyl)benzyl]amine and1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid by amethod analogous to that described in Example 17.

¹H-NMR (DMSO-d₆): δ 9.94 (1H, t); 8.37 (1H, d); 8.02 (1H, d); 7.93-7.68(5H, m); 7.54 (1H, d); 6.61 (1H, d); 4.55 (2H, d); 3.33 (3H, s).

APCI-MS m/z: 543.2, 545.2 [MH⁺].

EXAMPLE 23N-[3-Cyano-4-(methylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-carboxamidea) 5-Formyl-2-(methylthio)benzonitrile

The subtitle compound was prepared analogously to Example 22a but atroom temperature for 1 h instead of heating the reaction mixture.

¹H-NMR (400 MHz, CDCl₃): δ 9.94 (1H, s); 8.07 (1H, d, J 1.7 Hz); 8.01(1H, dd, J 8.3, 1.8 Hz); 7.40 (1H, d, J 8.3 Hz); 2.64 (3H, s).

GC-MS m/z: 177 [M⁺].

b) 5-(Hydroxymethyl)-2-(methylthio)benzonitrile

The subtitle compound was prepared analogously to Example 22b.

¹H NMR (400 MHz, CDCl₃): δ 7.62 (1H, s); 7.53 (1H, d, J 8.3 Hz); 7.32(1H, d, J 8.3 Hz); 4.70 (2H, s); 2.57 (3H, s).

c) S-(Hydroxymethyl)-2-(methylsulfonyl)benzonitrile

The subtitle compound was prepared analogously to Example 22c.

¹H-NMR (400 MHz, CDCl₃): δ 8.17 (1H, d, J 8.1 Hz); 7.93 (1H, s); 7.79(1H, d, J 8.2 Hz); 4.88 (2H, s); 3.27 (3H, s).

d) 5-(Bromomethyl)-2-(methylsulfonyl)benzonitrile

The subtitle compound was prepared analogously to Example 22d.

¹H NMR (400 MHz, CDCl₃): δ 8.18 (1H, d, J 8.1 Hz); 7.93 (1H, d, J 1.7Hz); 7.82 (1H, dd, J 8.2, 1.6 Hz); 4.51 (2H, s); 3.29 (3H, s).

e) 5-(Aminomethyl)-2-(methylsulfonyl)benzonitrile

The subtitle compound was prepared analogously to Example 22e.

¹H-NMR (400 z, CD₃OD): δ 8.14 (1H, d, J 8.2 Hz); 8.04 (1H, s); 7.88 (1H,d, J 8.1 Hz); 3.97 (2H, s); 3.29 (3H, s)

APCI-MS m/z: 211 [MH⁺].

f)N-[3-Cyano-4-(methylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was prepared analogously to Example 17.

¹H-NMR (400 MHz, CDCl₃): δ 10.19 (1H t, J 5.7 Hz); 8.56 (1H, d, J 7.4Hz); 8.11 (1H, d, J 8.1 Hz); 7.85-7.71 (4H, m); 7.53 (1H, s); 7.46 (1H,d, J 8.0 Hz); 6.51 (1H, d, J 7.5 Hz); 4.71 (1H, dd, J 15.9, 6.2 Hz);4.65 (1H, dd, J 15.9, 6.0 Hz); 3.23 (3H, s); 2.11 (3H, s).

APCI-MS m/z: 490 [MH⁺].

EXAMPLE 246-Methyl-N-[3-methyl-4(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamidea) 3-Methyl-4-(methylthio)benzaldehyde

The subtitle compound was prepared analogously to Example 22a.

GC-MS m/z: 166 [M⁺].

b) [3-Methyl-4-(methylthio)phenyl]methanol

The subtitle compound was prepared analogously to Example 22b.

¹H-NMR (300 MHz, CDCl₃): δ 7.18-7.09 (3H, m); 4.57 (2H, s); 2.44 (3H,s); 2.32 (3H, s).

c) [3-Methyl-4-(methylsulfonyl)phenyl]methanol

The subtitle compound was prepared analogously to Example 22c.

¹H-NMR (300 MHz, CDCl₃): δ 7.92 (1H, d, J 18.7 Hz); 7.35-7.29 (2H, m);4.73 (2H, s); 3.05 (3H, s); 2.66 (3H, s).

d) 4-(Bromomethyl)-2-methyl-1-(methylsulfonyl)benzene

The subtitle compound was prepared analogously to Example 22d.

¹H-NMR (300 MHz, CDCl₃): δ 8.00 (1H, d, J 8.1 Hz); 7.42-7.28 (2H, m);4.46 (2H, s); 3.07 (3H, s); 2.70 (3H, s).

e) [3-Methyl-4-(methylsulfonyl)benzyl]amine

The subtitle compound was prepared analogously to Example 22e.

¹H-NMR (400 MHz, CDCl₃): δ 7.98 (1H, d, J 8.2 Hz); 7.35-7.29 (2H, m);3.93 (2H, s); 3.06 (3H, s); 2.70 (3H, s).

APCI-MS m/z: 200 [MH⁺].

f)6-Methyl-N-[3-methyl-4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was prepared analogously to Example 17.

¹H-NMR (300 MHz, CDCl₃): δ 9.91 (1H, bt, J 5.7 Hz); 8.58 (1H, d, J 7.5Hz); 795 (1H, d, J 8.1 Hz); 7.83-7.27 (6H, m); 6.47 (1H, dd, J 7.5, 0.5Hz); 4.68-4.53 (2H, m); 3.03 (3H, s); 2.66 (3H, s); 2.08 (3H, s).

APCI-MS m/z: 479 [MH⁺].

EXAMPLE 256-Methyl-N-[4-(methylthio)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

6-Methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid (1.29 g, 4.35 mmol) and [4-(methylthio)benzyl]amine (0.66 g, 4.35mmol) were dissolved in NMP (18 ml). HBTU (1.81 g, 4.79 mmol) and DIEA(1.86 ml, 10.9 mmol) were added neat at room temperature and the mixturewas stirred overnight. The reaction mixture was poured into EtOAc. Theorganic phase was washed with 2.5% aqueous sodium carbonate, then threetimes with water and dried. Purification by flash-chromatography (EtOAc:cyclohexane 9:1) gave the title compound (1.3 g, 69%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.78 (1H, t, J 5.8 Hz); 8.38 (1H, d, J 7.4Hz); 7.91-7.69 (4H, m); 7.22 (4H, m); 6.62 (1H, d, J 7.6 Hz); 4.42 (2H,d, J 5.9 Hz); 2.43 (3H, s); 2.01 (3H, s).

APCI-MS m/z: 433.1 [MH⁺].

EXAMPLE 266-Methyl-N-[4-(methylsulfinyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

6-Methyl-N-[4-(methylthio)benzyl]-2-oxo-1-[3-trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(1.26 g, 2.93 mmol) was dissolved in CH₂Cl₂ (12 ml). The solution wascooled to −15° C. To the stirred solution 3-chloroperoxybenzoic acid(672 mg, 2.93 mmol) was added portion wise. The reaction was stirred for1 h. The cooling bath was removed and the reaction was allowed to reachroom temperature. After 2 h, CH₂Cl₂ and diluted sodium thiosulphatesolution were added. The mixture was shaken and the water phase wasseparated. The organic layer was washed twice with saturated NaHCO₃,once with brine and finally dried. Purification by flash-chromatography(EtOAc: MeOH 9:1) gave the title compound (1.1 g, 80%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.88 (1H, t, J=5.9 Hz); 8.38 (1H, d, J 7.5Hz); 7.93-7.69 (4H, m); 7.62 (2H, d, J 8.2 Hz); 7.47 (2H, d, J 8.2 Hz);6.62 (1H, d, J 7.7 Hz); 4.54 (2H, d, J 6.0 Hz); 2.70 (3H, s); 2.02 (3H,s).

APCI-MS m/z: 449.1 [MH⁺].

EXAMPLE 27N-[4-(Benzylsulfonyl)benzyl-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidea)N-(4-Mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

6-Methyl-N-[4-(methylsulfinyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(0.30 g, 0.67 mmol) was dissolved in dry acetonitrile (3 ml) and2,6-lutidine (0.24 ml, 2.08 mmol) was added. The solution was cooled to−20° C. and trifluoroacetic anhydride (0.28 ml, 2.0 mmol) was added. Thereaction was kept between −10° C. and 0° C. for 1 h, and then allowed toreach room temperature. All volatile materials were evaporated at 30° C.The crude residue was cooled to 0° C. A degassed, dry 1:1 mixture oftriethylamine (1.1 ml) and methanol (1.1 ml), cooled to 0° C., wasadded. The reaction was stirred at room temperature for 30 min and thenevaporated. The residue was dissolved in a 1:1 mixture of methanol and6M hydrochloric acid and stirred at 50° C. for 20 min. The major part ofthe solvent was evaporated. Ethyl acetate and water were added. Thewater phase was separated and washed again with ethyl acetate. Thecombined organic phase was washed with brine, dried, evaporated and usedas crude product in the next step.

LC-MS; method B RT: 8.19 min. APCI-MS m/z: 419.3 [MH⁺].

b)N-[4-(Benzylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

In an argon filled vialN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) was dissolved in dried, degassed ethanol (0.1 ml) andcooled to 0° C. A solution of potassium tert-butoxide (7.8 mg, 0.7 mmol)in ethanol (0.2 ml) was added. The reaction was stirred for 45 min.(Bromomethyl)benzene (12 μl, 0.105 mmol) in ethanol (0.1 ml) was added.The ice bath was removed and the reaction was stirred overnight. Amixture of ethyl acetate and 1M aqueous NH₄Cl was added. The organiclayer was separated, dried and evaporated. The residue was dissolved inCH₂Cl₂ (240 μl) and cooled with stirring to −15° C.3-Chloroperoxybenzoic acid (35 mg, 0.154 mmol) in CH₂Cl₂ (200 μl) wasadded. The cooling bath was removed and the reaction was stirredovernight. EtOAc and 5% aqueous sodium thiosulfate were added. Theorganic layer was separated, washed with 5% aqueous sodium carbonate,brine and dried. Purification by preparative HPLC gave the titlecompound (11 mg, 30%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.91 (1H, t, J 6.1 Hz); 8.38 (1H, d, J 7.5Hz); 7.81 (4H, m); 7.66 (2H, d, J 8.4 Hz); 7.46 (2H, d, J 8.2 Hz);7.31-7.11 (5H, m); 6.63 (1H, d, J 7.6 Hz); 4.62 (2H, s); 4.57 (2H, d, J6.1 Hz); 2.03 (3H, s).

APCI-MS m/z: 541.4 [MH⁺].

Following the general method of Example 27 (b), the compounds ofExamples 28 to 33 were prepared:

EXAMPLE 286-Methyl-2-oxo-N-[4-(propylsulfonyl)benzyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

FromN-(4mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and 1-bromopropane (10 μl, 0.105 mmol). Yield: 12 mg(35%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.93 (1H, t, J 6.1 Hz); 8.38 (1H, d, J 7.5Hz); 7.94-7.70 (6H, m); 7.53 (2H, d, J 8.2 Hz); 6.63 (1H, d, J 7.6 Hz);4.58 (2H, d, J 6.1 Hz); 3.22 (2H, m); 2.02 (3H, s); 1.52 (2H, q, J=7.6Hz); 0.89 (3H, t, J=7.4 Hz).

APCI-MS m/z: 493.3 [MH⁺.

EXAMPLE 29N-[4(Butylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and 1-bromobutane (11 μl, 0.105 mmol). Yield: 14 mg,0.028 mmol (39%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.93 (1H, t, J=6.1 Hz); 8.38 (1H, d, J 7.4Hz); 7.93-7.70 (6H, m); 7.53 (2H, d, J 8.3 Hz); 6.63 (1H, d, J 7.7 Hz);459 (2H, d, J 6.1 Hz); 3.24 (2H, m); 2.02 (3H, s); 1.48 (2H, m); 1.31(2H, m); 0.81 (3H, t, J=7.3 Hz).

APCI-MS m/z: 507.3 [MH⁺].

EXAMPLE 30N-[4-(Isobutylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

FromN-(4mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-'sdihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and1-bromo-2-methylpropane (11 μl, 0.105 mmol). Yield: 10 mg, 0.020 mmol(28%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.93 (1H, t, J 6.0 Hz); 8.38 (1H, d, J 7.5Hz); 7.94-7.69 (6H, m); 7.53 (2H, d, J 8.3 Hz); 6.63 (1H, d, J 7.7 Hz);4.58 (2H, d, J 6.2 Hz); 3.16 (2H, d, J 6.5 Hz); 2.02 (3H, s); 1.96 (1H,quintet, J=6.6 Hz); 0.95 (6H, d, J 6.7 Hz).

APCI-MS m/z: 507.3 [MH⁺].

EXAMPLE 31N-[4-(sec-Butylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and 2-brombutane (11 μl, 0.105 mmol). Yield: 12 mg,0.024 mmol (35%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.94 (1H, t, J=6.0 Hz); 8.38 (1H, d, J 7.5Hz); 7.93-7.69 (6H, m); 7.53 (2H, d, J 8.2 Hz); 6.63 (1H, d, J 7.8 Hz);4.59 (2H, d, J 6.1 Hz); 3.17 (1H, dq, J 13.4, 6.7 Hz); 2.02 (3H, s);1.77 (1H, m); 1.29 (1H, m); 1.11 (3H, d, J 6.9 Hz); 0.89 (3H, t, J=7.5Hz).

APCI-MS m/z: 507.4 [MH⁺].

EXAMPLE 32N-[4-(Isopropylsulfonyl)benzyl]-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and 2-bromopropane (10 μl, 0.105 mmol). Yield. 11 mg,0.022 mmol (33%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.94 (1H, t, J 6.1 Hz); 8.38 (1H, d, J 7.4Hz); 7.94-7.69 (6H, m); 7.54 (2H, d, J 8.3 Hz); 6.63 (1H, d, J 7.7 Hz);4.60 (2H, d, J 6.1 Hz); 3.36 (1H, septet, J 6.2 Hz); 2.03 (3H, s); 1.13(6H, d, J 6.8 Hz).

APCI-MS m/z: 493.3 [MH⁺].

EXAMPLE 336-Methyl-N-{4-[(3-methylbutyl)sulfonyl]benzyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-[3(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and 1-bromo-3-methylbutane (13 μl, 0.105 mmol).Yield: 11 mg, 0.021 mmol (31%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.93 (1H, t, J=6.1 Hz); 8.38 (1H, d, J 7.4Hz); 7.94-7.69 (6H, m); 7.53 (2H, d, J 8.3 Hz); 6.63 (1H, d, J 7.5 Hz);4.59 (2H, d, J 6.1 Hz); 3.23 (2H, m); 2.02 (3H, s); 1.57 (1H, septet,J=6.8 Hz); 1.39 (2H, m); 0.80 (6H, d, J 6.6 Hz).

APCI-MS m/z: 521.4 [MH⁺].

Following the general method of Example 27, the compounds of Examples 34to 52 were prepared:

EXAMPLE 34N-{4-[(Cyclopropylmethyl)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-(3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and (bromomethyl)cyclopropane (10 μl, 0.105 mmol).Yield: 13 mg, 0.027 mmol (38%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.93 (1H, t, J=6.2 Hz); 8.38 (1H, d, J 7.5Hz); 7.93-7.70 (6H, m); 7.53 (2H, d, J 8.3 Hz); 36.63 (1H, d, J 7.6 Hz);4.59 (2H, d, J 6.1 Hz); 3.21 (2H, d, J 7.2 Hz); 2.02 (3H, s); 0.80 (1H,m); 0.43 (2H, m); 0.09 (2H, m).

APCI-MS m/z: 505.3 [MH⁺].

Example 356-Methyl-2-oxo-N-{4-[(tetrahydrofuran-2-ylmethyl)sulfonyl]-benzyl}-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and 2-(bromomethyl)tetrahydrofuran (12 μl, 0.105mmol). Yield: 8 mg, 0.015 mmol (22%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.93 (1H, t, J 6.0 Hz); 8.38 (1H, d, J 7.5Hz); 7.93-7.70 (6H, m); 7.51 (2H, d, J 8.2 Hz); 6.63 (1H, d, J 7.6 Hz);4.58 (2H, d, J 6.1 Hz); 4.05 (1H, quintet, J=6.5 Hz); 3.59 (1H, q, J 7.4Hz); 3.50 (3H, m); 2.02 (3H, s); 1.94 (1H, m); 1.75 (2H, m); 1.54 (1H,m).

APCI-MS m/z: 535.4 [MH⁺].

EXAMPLE 36N-{4-[(2-Hydroxyethyl)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-(3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 nmol) and 2-bromoethanol (7 μl, 0.105 mmol). Yield: 12 mg,0.025 mmol (36%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.93 (1H, t, J=6.1 Hz); 8.38 (1H, d, J 7.4Hz); 7.93-7.70 (6H, m); 7.52 (2H, d, J 8.3 Hz); 6.63 (1H, d, J 7.6 Hz);4.58 (2H, d, J 6.1 Hz); 3.65 (2H, t, J=6.4 Hz); 3.40 (2H, t, J=6.5 Hz);2.02 (3H, s).

APCI-MS m/z: 495.3 [MH⁺].

EXAMPLE 37N-{4-[(Cyanomethyl)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

FromN-(4-mercaptobenzyl)methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and chloroacetonitrile (7 μl, 0.105 mmol). Yield: 8mg, 0.017 mmol (24%).

¹H-NMR (400 MHz, DMSO-4) δ 9.96 (1H, t, J=6.1 Hz); 8.37 (1H, d, J 7.5Hz); 7.95-7.69 (6H, m); 7.62 (2H, d, J 8.3 Hz); 6.63 (1H, d, J 7.6 Hz);5.20 (2H, s); 4.61 (2H, d, J=6.2 Hz); 2.03 (3H, s).

APCI-MS m/z: 490.3 [MH⁺].

EXAMPLE 38N-{4-[(2-Amino-2-oxoethyl)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-(3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and 2-bromoacetamide (14 mg, 0.105 mmol). Yield: 15mg, 0.029 nmol (41%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.94 (1H, t, J=6.1 Hz); 8.38 (1H, d, J 7.4Hz); 7.95-7.46 (10H, m); 6.62 (1H, d, J 7.6 Hz); 4.58 (2H, d, J 6.0 Hz);4.18 (2H, s); 2.02 (3H, s).

APCI-MS m/z: 508.3 [MH⁺].

EXAMPLE 39N-{4-[(4-Cyanobenzyl)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and 4-(bromomethyl)benzonitrile (21 mg, 0.105 mmol).Yield: 3 mg, 0.004 mmol (6%).

LC-MS; method B RT: 7.80 nm, APCI-MS m/z: 566.4 [MH⁺].

EXAMPLE 40N-{4-[(2-Cyanoethyl)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and 3-chloropropanenitrile (8 μl, 0.105 mmol). Yield:1 mg, 0.002 mmol (3%).

LC-MS; method B RT: 7.16 min, APCI-MS m/z: 504.3 [MH⁺].

EXAMPLE 41N-{4-[(3-Hydroxypropyl)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-[3-trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and 3-bromopropan-1-ol (9 μl, 0.105 mmol). Yield: 6mg, 0.012 mmol (18%).

LC-MS; method B RT: 6.40 min, APCI-MS m/z: 509.3 [MH⁺].

EXAMPLE 42N-(4-{[2(Dimethylamino)-2-oxoethyl]sulfonyl}benzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and 2-chloro-N,N-dimethylacetamide (11 μl, 0.105mmol). Yield: 10 mg, 0.019 mmol (27%).

LC-MS; method B RT: 6.61 min, APCI-MS m/z: 536.4 [MH⁺].

EXAMPLE 43 Ethyl3-[(4-{[([{6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-yl}carbonyl)amino]methyl}phenyl)sulfonyl]propanoate

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluorometbyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and ethyl 3-bromopropanoate (13 μl, 0.105 mmol).Yield: 5 mg, 0.009 mmol (13%).

LC-MS; method B RT: 7.64 min, APCI-MS m/z: 551.4 [MH⁺].

EXAMPLE 442-[(4-{[({6-Methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-yl}carbonyl)amino]methyl}phenyl)sulfonyl]ethylacetate

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and 2-bromoethyl acetate (12 μl, 0.105 mmol). Yield.7 mg, 0.014 mmol (20%).

LC-MS; method B RT: 7.19 min, APCI-MS m/z: 537.3 [MH⁺].

EXAMPLE 45N-{4-[(3-Cyanobenzyl)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and 3-(bromomethyl)benzonitrile (21 mg, 0.105 mmol).Yield: 2 mg, 0.004 mmol (6%).

LC-MS; method B RT: 7.77 min, APCI-MS m/z: 566.3 [MH⁺].

EXAMPLE 46 Methyl3-[(4-{[({6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-yl}carbonyl)amino]methyl}phenyl)sulfonyl]propanoate

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and methyl 3-bromopropanoate (11 μl, 0.105 mmol).Yield: 2 mg, 0.005 mmol (7%).

LC-MS; method B RT: 7.28 min, APCI-MS m/z: 537.3 [MH⁺].

EXAMPLE 476-Methyl-N-(4-{[(2-methyl-1,3-thiazol-4-yl)methyl]sulfonyl}benzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidetrifluoroacetate

FromN-4-mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and 4-(chloromethyl)-2-methyl-1,3-thiazolehydrochloride (19 mg, 0.105 mmol). Yield: 11 mg, 0.017 mmol (24%).

LC-MS; method B RT: 7.21 min, APCI-MS m/z: 562.3 [MH⁺].

EXAMPLE 486-Methyl-2-oxo-N-{4-[(pyridin-4-ylmethyl)sulfonyl]benzyl}-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidetrifluoroacetate

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and 4-chloromethyl)pyridine hydrochloride (17 mg,0.105 mmol). Yield: 5 mg, 0.008 mmol (11%).

LC-MS; method B RT: 5.79 min, APCI-MS m/z: 542.3 [MH⁺].

EXAMPLE 49N-{4-[(3-Cyanopropyl)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

FromN-(4mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and 4-bromobutanenitrile (10 μl, 0.105 mmol). Yield:11 mg, 0.022 mmol (31%).

LC-MS; method B RT: 7.19 min, APCI-MS m/z: 518.3 [MH⁺].

EXAMPLE 50N-(4-{[(3,5-Dimethylisoxazol-4-yl)methyl]sulfonyl}benzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidetrifluoroacetate

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and 4-(chloromethyl)-3,5-dimethylisoxazole (13 μl,0.105 mmol). Yield: 9 mg, 0.013 mmol (19%).

LC-MS; method B RT: 750 min, APCI-MS m/z: 560.4[MH⁺].

EXAMPLE 51N-(4-{[4(Acetylamino)benzyl]sulfonyl}benzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and N-[4(chloromethyl)phenyl]-acetamide (19 mg, 0.105mmol). Yield: 7 mg, 0.013 mmol (18%).

LC-MS; method B RT: 6.98 min, APCI-MS m/z: 598.4 [MH³⁰].

EXAMPLE 526-Methyl-N-[4-({2-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]-2-oxoethyl}sulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

FromN-(4-mercaptobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(29 mg, 0.07 mmol) and2-bromo-N-(5-methyl-1,3,4-thiadiazol-2-yl)acetamide (25 mg, 0.105 mmol).Yield: 4 mg, 0.006 mmol (9%).

LC-MS; method B RT: 6.62 min, APCI-MS m/z: 606.2 [MH³⁰].

EXAMPLE 536-Methyl-N-[4-(methylsulfonyl)phenoxy]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

To a mixture of6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid (67 mg, 0.22 mmol), HATU (93.7 mg, 0.25 mmol), HOAT (34 mg, 0.25mmol), DIEA (150 μl, 0.87 mmol) and NMP (2 ml) was addedO-[4-(methylsulfonyl)phenyl]hydroxylamine, prepared according to theprocedure in J. Med. Chem., 1967, 512 (41 mg, 0.22 mmol). After stirringat room temperature for 3 h the mixture was partitioned between EtOAcand water. The organic extract was washed with brine, dried, filteredand evaporated to dryness. The crude product was further purified bypreparative HPLC to give the title compound as a white solid (41 mg,40%).

¹H-NMR (CDCl₃):

12.19 (1H, s); 8.58 (1H, d, J 7.4 Hz); 7.92-7.86 (3H, m); 7.80 (1H, t, J7.9 Hz); 7.57 (1H, s); 7.50 (1H, d, J 7.9 Hz); 7.30-7.26 (5H, m); 6.56(1H, d, J 7.5 Hz); 3.03 (3H, s); 2.16 (3H, s).

APCI-MS m/z: 567 [MH⁺].

EXAMPLE 546-Methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid (4-bromo-phenoxy)-amide

A solution of6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid (0.060 g, 0.20 mmol) in CH₂Cl₂ (5 ml) and SOCl₂ (5 ml) was stirredfor 3 h at room temperature and then concentrated to give the crudeintermediate acid chloride as a solid. The solid was dissolved in1,4-dioxane and O-(4-bromo-phenyl)-hydroxylamine, prepared according tothe procedure in J. Med. Chem., 1967, 512, (0.10 g, 0.53 mmol) was addedand the mixture was stirred at room temperature for 10 min. Thevolatiles were removed and the residue was purified on preparative HPLC,giving 0.055 g (58%) of the title compound as an off-white solid.

¹H-NMR (CDCl₃): δ 12.08 (1H, s); 8.57 (1H, d, J 7.42 Hz); 7.84 (1H, d, J8.01 Hz); 7.77 (1H, t, J 8.01 Hz); 7.55 (1H, s); 7.47 (1H, d, J 8.01Hz); 7.38 (2H, d, J 8.87 Hz); 7.00 (2H, 8.90 Hz); 6.52 (1H, d, J 7.48Hz); 2.13 (3H, s)

APCI-MS m/z: 467.1 and 469.0 [MH⁺].

EXAMPLE 556-Methyl-2-oxo-N-phenoxy-1-[3(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was prepared as described in Example 53 starting formO-phenyl hydroxylamine.

¹H-NMR (CDCl₃): δ 12.04 (1H, s); 8.58 (1H, d); 7.85-7.74 (2H, m); 7.55(1H, brs); 7.48 (1H, d); 7.32-7.26 (2H, m); 7.12 (2H, d); 7.02 (1H, t);6.51 (1H, d); 2.12 (3H, s).

APCI-MS m/z: 389 [MH⁺].

EXAMPLE 56N-(4-Aminobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroproline-3-carboxamide

To a mixture of1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (212 mg,0.7 mmol), HATU (272 mg, 0.7 mmol), HOAT (97 mg, 0.7 mmol) and DIEA (275mg, 2.13 mmol) in NMP (3 ml) was added (4-aminobenzyl)amine (87 mg, 0.7mmol) in NMP (1 ml). The reaction was stirred for 12 h at roomtemperature. The reaction mixture was diluted with water (1.0 ml) andpurified on a Xterra@Prep MS C8 column (19×50 mm) using a gradient ofCH₃CN/water at a flow rate of 20 ml/min. Freeze drying of the mixtureafforded the title compound (140 mg, 49%).

¹H-NMR (400 MHz, CDCl₃), δ 9.74 (1H, t, J=5.4 Hz), 8.56 (1H, d, J 7.5Hz), 7.78 (1H, m), 7.50 (1H, s), 7.43 (1H, d, J 7.8 Hz), 7.27 (1H, s),7.15 (2H d, J 8.1 Hz), 6.81 (2H, d, J 8.2 Hz), 6.43 (1H, d, J 7.4 Hz),4.49 (2H, m), 2.06 (3H, s, J 9.1 Hz)

APCI-MS m/z: 402.2 [MH⁺].

EXAMPLE 576-Methyl-N-{4-[(methylsulfonyl)amino]benzyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

To a mixture ofN-(4-aminobenzyl)-6-methyl-2,4-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroproline-3-carboxamide(80 mg, 0.2 mmol) in CH₂Cl₂, methanesulfonyl chloride (23 mg, 0.2 mmol)and DIEA (26 mg, 0.2 mmol) were added. The reaction mixture was stirredfor 0.5 h at room temperature. The CH₂Cl₂ was evaporated off and theresidue dissolved in CH₃CN/water and purified on a Xterra@Prep MS C8column (19×50 mm) using a gradient of CH₃CN/water at a flow rate of 20ml/min. Freeze drying of the mixture afforded the title compound (67 mg,70%).

¹H-NMR (400 MHz, CDCl₃) δ 9.83 (1H, s), 8.59 (1H, d, J 7.4 Hz), 7.80(1H, d, J 7.9 Hz), 7.73 (1H, t, J 7.8 Hz), 7.51 (1H, s), 7.43 (1H, d, J7.9 Hz), 7.31 (2H, d, J 8.4 Hz), 7.14 (2H, d, J 8.4 Hz), 6.46 (1H, d, J7.4 Hz), 6.38 (1H, s), 4.57 (m, 1H), 2.97 (3H, s, J=3.9 Hz), 2.08 (3H,s, J=4.3 Hz).

APCI-MS m/z: 480.1 [MH⁺].

EXAMPLE 58N-{4-[Bis(methylsulfonyl)amino]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was isolated as a by-product using the methoddescribed in Example 57.

¹H-NMR (400 MHz, CDCl₃): δ 9.94 (t, J=5.6 Hz, 1H), 8.59 (d, J 7.4 Hz,1H), 7.82 (d, J 7.9 Hz, 1H), 7.75 (t, J 7.8 Hz, 2H), 7.53 (s, 1H), 7.45(t, J 5.6 Hz, 3H), 7.29 (d, J 9.7 Hz, 2H); 6.47 (d, J 7.5 Hz, 1H), 4.64(t, J 5.1 Hz, 2H), 3.39 (s, 6H), 2.09 (s, 3H).

APCI-MS m/z: 558.4 [MH⁺].

EXAMPLE 59N-[[4-[[(Dimethylamino)sulfonyl]amino]phenyl]methyl]-1,2-dihydro-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide

The title compound was prepared fromN-(4-aminobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroproline-3-carboxamideand dimethylsulfamoyl chloride (2 mg, 10%) following the method outlinedin Example 57.

¹H-NMR (400 MHz, CD₃OD) δ 8.48 (1H, d, J 7.5 Hz); 7.86 (1H, d, J 7.4Hz); 7.79 (2H, t, J 7.9 Hz); 7.73 (1H, s); 7.59 (1H, d, J 8.5 Hz); 7.25(2H, d, J 8.6 Hz); 7.17 (2H, d, J 8.5 Hz); 6.63 (1H, d, J 7.6 Hz); 4.52(2H, s); 2.74 (6H, s); 2.09 (3H, s).

APCI-MS m/z: 509.3 [MH⁺].

EXAMPLE 606-Methyl-N-{4-[methyl(methylsulfonyl)amino]benzyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

To a mixture of6-methyl-N-{4-[(methylsulfonyl)amino]benzyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(10 mg, 0.02 mmol) in dichloromethane, iodomethane (4 mg, 0.03 mmol) andDIEA (3.9 mg, 0.03 mmol) were added. The reaction was stirred for 10 minat 60° C. in a microwave oven. After evaporation of the solvent, theresidue was dissolved in CH₃CN/water and purified on a Xterra@Prep MS C8column (19×50 mm) using a gradient of CH₃CN/water at a flow rate of 20ml/min. Freeze drying of the mixture afforded the title compound (6 mg,60%).

¹H NMR (400 MHz, DMSO-d₆) δ 9.83 (1H, t, J 5.9 Hz), 8.38 (1H, d, J 7.5Hz), 7.89 (2H, d, J 8.7 Hz), 7.80 (1H, t, J 7.7 Hz), 7.71 (1H, d, J 8.0Hz), 7.32 (4H, m), 6.62 (1H, d, J 7.5 Hz), 4.48 (2H, d, J 5.9 Hz), 3.20(3H, s), 2.91 (3H, s), 2.01 (3H, s)

APCI-MS m/z: 494.1 [MH⁺].

Following the general method of Example 60, the compounds of Examples60.1 to 60.7 were prepared:

Example 60.1N-[[4-[Butyl(methylsulfonyl)amino]phenyl]methvl]-1,2-dihydro-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide

Using 1-iodobutane. Yield (7 mg, 43%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.86 (1H, s); 8.38 (1H, d, J 7.3 Hz); 7.89(2H, d, J 9.5 Hz); 7.80 (1H, t, J 7.4 Hz); 7.72 (1H, d, J 8.2 Hz); 7.32(4H, s); 6.63 (1H, d, J 7.2 Hz); 4.49 (2H, d, J 5.8 Hz); 3.58 (2H, s);2.91 (3H, s); 2.02 (3H, s); 1.27 (4H, s); 0.81 (3H, t, J 6.2 Hz).

APCI-MS m/z: 536.4 [MH⁺].

Example 60.21,2-Dihydro-6-methyl-N-[[4-[(1-methylethyl)(methylsulfonyl)-amino]phenyl]methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide

Using 2-iodopropane. Yield (10 mg, 38%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.88 (2H, t, J=6.0 Hz); 8.39 (2H, d, J 7.4Hz); 7.89 (4H, d, J 11.6 Hz); 7.80 (3H, t, J=7.8 Hz); 7.72 (2H, d, J 8.1Hz); 7.33 (411, d, J 8.3 Hz); 7.22 (4H, d, J 8.3 Hz); 6.63 (2H, d, J 7.6Hz); 4.52 (4H, d, J 6.1 Hz); 4.30 (2H, quintet, J=6.7 Hz); 3.02 (7H, s);2.02 (6H, s); 1.04 (12H, d, J 6.8 Hz).

APCI-MS m/z: 522.4 [MH⁺].

Example 60.3N-{4-[(2-Methoxyethyl)(methylsulfonyl)amino]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

Using 2-bromoethyl methyl ether. Yield (15 mg, 33%).

¹H NMR (400 MHz, DMSO-d₆) δ 9.86 (1H, t, J 5.9 Hz); 8.38 (1H, d, J 7.4Hz); 7.89 (2H d, J 9.3 Hz); 7.80 (1H, t, J 7.8 Hz); 7.72 (1H, d, J 7.9Hz); 7.32 (4H, d); 6.62 (1H, d, J 7.5 Hz); 4.49 (2H, d, J 6.0 Hz); 3.73(2H, t, J 5.8 Hz); 3.29 (2H, t, J 5.7 Hz); 3.17 (3H, s); 2.98 (3H, s);2.02 (3H, s).

APCI-MS m/z: 538.4 [MH⁺].

Example 60.4N-{4-[(2-Cyanoethyl)(methylsulfonyl)amino]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

Using 3-bromopropionitrile. Yield (3 mg, 19%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.86 (1H, t); 8.39 (1H, d, J 7.4 Hz); 7.89(2H, d, J 9.3 Hz); 7.80 (1H, t, J 0.0 Hz); 7.72 (1H, d, J 7.5 Hz); 7.36(4H, s); 6.63 (1H, d, J 7.5 Hz); 4.50 (2H, d, J 6.2 Hz); 3.86 (2H, t, J6.4 Hz); 3.00 (3H, s); 2.60 (2H, t, J=6.3 Hz); 2.02 (3H, s).

APCI-MS m/z: 533.1 [MH⁺].

Example 60.5N-{4-[Ethyl(methylsulfonyl)amino]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

Using iodoethane. Yield: (6 mg, 59%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.86 (1H, t, J=5.9 Hz); 8.38 (1H, d, J 7.4Hz); 7.89 (2H, d, J 9.3 Hz); 7.80 (1H, t, J 7.8 Hz); 7.72 (1H, d, J 8.1Hz); 7.32 (4H, dd, J 11.6, 8.7 Hz); 6.62 (1H, d, J 75 Hz); 4.49 (2H, d,J 6.0 Hz); 3.62 (2H, q, J 7.1 Hz); 2.93 (3H, s); 2.02 (3H, s); 0.96 (3H,t, J 7.1 Hz);

APCI-MS m/z: 508.4 [MH⁺].

Example 60.61,2-Dihydro-6-methyl-N-[[4[(methylsulfony)propylamino]-phenyl]methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide

Using 1-iodopropane. Yield (6 mg, 57%).

¹H NMR (400 MHz, DMSO-d₆) δ 9.86 (1H, t, J 6.0 Hz); 8.38 (1H, d, J 7.5Hz); 7.89 (2H, d, J 8.8 Hz); 7.80 (1H, t, J 7.8 Hz); 7.72 (1H, d, J 8.2Hz); 7.32 (4H, s); 6.62 (1H, d, J 7.7 Hz); 4.49 (2H, d, J 6.0 Hz); 3.54(2H, t, J 7.1 Hz); 2.92 (3H, s); 2.01 (3H, s); 1.31 (2H, q, J 7.2 Hz);0.80 (3H, t, J 7.3 Hz).

APCI-MS m/z: 522.4 [MH⁺].

Example 60.7N-[[4-[(3-Amino-3-oxopropyl)(methylsulfonyl)amino]phenyl]-methyl]-1,2-dihydro-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide

Using 3-bromopropionamide. Yield (7 mg, 30%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.86 (1H, t, J 6.0 Hz); 8.39 (1H, d, J 7.5Hz); ∂7.89 (2H, d, J 10.5 Hz); 7.80 (1H, t, J 7.7 Hz); 7.72 (1H, d, J7.8 Hz); 7.32 (5H, dd, J 11.0, 8.8 Hz); 6.81 (1H, s); 6.63 (1H, d, J 7.6Hz); 4.50 (2H, d, J 6.0 Hz); 3.80 (2H, t, J 7.5 Hz); 2.96 (3H, s); 2.17(2H, t, J 7.6 Hz); 2.02 (3H, s).

APCI-MS m/z: 551.4 [MH⁺].

EXAMPLE 611,2-Dihydro-6-methyl-N-[[4-[(methylsulfonyl)oxy]phenyl]methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamidea)N-(4-Hydroxybenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

To a mixture of1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (1 g,3.36 mmol), HATU (1.28 g, 3.36 mmol), HOAT (457 mg, 3.36 mmol) and DIEA(1.7 g, 13.36 mmol) in NMP (10 ml) was added (4-hydroxybenzyl)aminehydrobromide (686 mg, 3.36 mmol) in NMP (5 ml). The reaction was stirredfor 12 h at room temperature. The reaction mixture was diluted withwater (75.0 ml) and extracted with EtOAc. The organic phase was dried(MgSO₄), filtered and evaporated affording the title compound (1.2 g,89%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.66 (1H, t, J 5.7 Hz); 9.27 (1H, s); 8.36(1H, d, J 7.4 Hz); 7.86 (2H, d, J 4.5 Hz); 7.78 (1H, t, J 8.0 Hz); 7.68(1H, d, J 7.9 Hz); 7.06 (2H, d, J 8.3 Hz); 6.67 (2H, d, J 8.5 Hz); 6.60(1H, d, J 7.4 Hz); 4.33 (2H, d, J 5.8 Hz); 1.99 (3H, s).

APCI-MS m/z: 403.3 [MH⁺].

b)1,2-Dihydro-6-methyl-N-[[4-[(methylsulfonyl)oxy]phenyl]methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide

The title compound was prepared fromN-(4-hydroxybenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamideand methansulfonyl chloride as in Example 57 (200 mg, 84%).

¹H NMR (400 MHz, DMSO-4) δ 9.87 (1H, t, J 6.0 Hz); 8.38 (1H, d, J 7.5Hz); 7.89 (2H, d, J 8.9 Hz); 7.80 (1H, t, J 7.8 Hz); 7.72 (1H, d, J 7.9z); 7.39 (2H, d, J 8.6 Hz); 7.29 (2H, d, J 8.6 Hz); 6.62 (1H, d, J 7.5Hz); 4.50 (2H, d, J 6.0 Hz); 3.35 (3H, s); 2.02 (3H, s).

APCI-MS m/z: 481.3 [MH⁺].

EXAMPLE 62 2-Propanesulfonic acid,4-[[[[1,2-dihydro-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyridinyl]carbonyl]amino]methyl]phenylester

The title compound was prepared fromN-(4-hydroxybenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamideand isopropylsulfonyl chloride as in Example 57.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.83 (1H, t); 8.35 (1H, d, J 7.5 Hz); 7.86(2H, d, J 8.7 Hz); 7.78 (1H, t, J 7.7 Hz); 7.69 (1H, d, J 7.3 Hz); 7.35(2H, d, J 8.5 Hz); 7.22 (2H, d, J 8.6 Hz); 6.60 (1H, d, J 7.3 Hz); 4.46(2H, d, J 6.2 Hz); 3.66 (1H, m); 1.99 (3H, s); 1.38 (6H, d, J 6.9 Hz).

APCI-MS m/z 509.4 [MH⁺].

EXAMPLE 63N-[(1,1-Dioxido-2,3-dihydro-1-benzothien-5-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidea) 2,3-Dihydro-1-benzothiophene-5-carbaldehyde and2,3-Dihydro-1-benzothiophene-7-carbaldehyde

The subtitle compounds were prepared according to the proceduredescribed in WO 01/12602.

b) 2,3-Dihydro-1-benzothien-5-ylmethanol and2,3-Dihydro-1-benzothien-7-ylmethanol

The title compounds were prepared by stirring a mixture of2,3-dihydro-1-benzothiophene-5-carbaldehyde and2,3-dihydro-1-benzothiophene-7-carbaldehyde (4,3 g, 26 mmol) with sodiumborohydride (3.78 g, 100 mmol) in THF (100 ml) and water (10 ml) at roomtemperature overnight. 1M Hydrochloric acid was added slowly to quenchthe excess of borohydride. The mixture was extracted with EtOAc andwashed with water. The solvents were removed in vacuo and the residuepurified by column chromatography on silica using heptane/EtOAc (4:1) aseluent to afford 2,3-dihydro-1-benzothien-5-ylmethanol (1.84 g):

¹H-NMR (CDCl₃): δ 7.22 (1H, brs); 7.20 (1H, d, J 8.3 Hz); 7.11 (1H, brd,J 8.3 Hz); 4.61 (2H, s); 3.41-3.25 (4H, m); and2,3-dihydro-1-benzothien-7-ylmethanol (1.18 g) (total yield 70%):

¹H-NMR (CDCl₃): δ 7.18 (1H, d, J 7.5 Hz); 7.15 (1H, d, J 7.5 Hz); 7.05(1H, t, J 7.5 Hz); 4.63 (2H, s); 3.41-3.28 (4H, m).

c) 1,1-Dioxido-2,3-dihydro-1-benzothien-5-yl)methanol

The title compound was prepared by stirring2,3-dihydro-1-benzothien-5-ylmethanol (1.08 g, 6.38 mmol), oxone (5.8 g,9.4 mmol), aqueous EDTA (22 ml, 0.4 mM), and sodium hydrogen carbonate(4.8 g) in a mixture of acetone and water at pH 7.5 at room temperatureovernight. The reaction mixture was extracted with EtOAc and washed withwater. The solvents were removed in vacuo and the residue purified bycolumn chromatography on silica using heptane/EtOAc (4:1) as eluent toafford the subtitle compound (1.0 g, 79%).

¹H-NMR (CDCl₃): δ7.70 (1H, d, J 7.9 Hz); 7.43 (1H, d, J 7.9 Hz); 7.42(1H, s); 4.79 (2H, s); 3.53-3.36 (4H, m).

d) 5-(Bromomethyl)-2,3-dihydro-1-benzothiophene 1,1-dioxide

The title compound was prepared by refluxing(1,1-dioxido-2,3-dihydro-1-benzothien-5-yl)methanol (1.0 g, 5 mmol) withphosphorus tribromide (0.524 g, 0.188 ml, 2 mmol) in dry toluene (20 ml)for 1 h. Water was added and the crude mixture was extracted with EtOAc,washed with water and brine and dried. The solvents were removed invacuo to afford the subtitle compound (1.15 g, 88%).

¹H NMR (CDCl₃): δ 7.73 (1H, d, J 8.0 Hz); 7.51 (1H, d, J 8.0 Hz); 7.43(1H, s); 4.51 (2H, s); 3.53 (2H, t, J 6.8 Hz); 3.43 (2H, t, J 6.8 Hz).

e) (1,1-Dioxido-2,3-dihydro-1-benzothien-5-yl)methylamine

The title compound was prepared by stirring5-bromomethyl)-2,3-dihydro-1-benzothiophene 1,1-dioxide (1.14 g, 4.36mmol) with aqueous ammonia (43 nml) in methanol/THF 1:1 (30 ml)overnight The solvents were removed in vacuo to afford the subtitlecompound (700 mg, 81%).

¹H-NMR (CDCl₃): δ 8.05 (2H, brs); 7.82 (1H, d, J 8.3 Hz); 7.63 (1H, s);7.61 (1H, d, J 8.3 Hz); 4.15 (2H, s); 3.62 (2H, t, J 6.9 Hz); 3.36 (2H,t, J 6.9 Hz).

APCI-MS m/z: 198 [MH⁺].

f)N-[(1,1-Dioxido-2,3-dihydro-1-benzothien-5-yl)methyl]-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

Starting from6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid (743 mg, 2.5 mmol) and(1,1-dioxido-2,3-dihydro-1-benzothien-5-yl)methylamine (500 mg, 2.5mmol) using the method described in Example 17, the title compound (1.05g, 88%) was obtained.

¹H-NMR (CDCl₃): δ 9.94 (1H, brt, J=6.0 Hz); 8.39 (1H, d, J 7.5 Hz); 7.93(1H, s); 7.91 (1H, d, J 7.7 Hz); 7.83 (1H, t, J 7.7 Hz); 7.74 (1H, d, J7.7 Hz); 7.70 (1H, d, J 8.0 Hz); 7.45 (1H, d, J 8.0 Hz); 7.43 (1H, s);6.64 (1H, d, J 7.5 Hz); 4.58 (2H, d, J 6.0 Hz); 3.57 (2H, t, J 6.9 Hz);3.34 (2H, t, J 6.9 Hz); 2.04 (3H, s).

APCI-MS m/z: 477 [MH⁺].

EXAMPLE 64N-[(1,1-Dioxido-2,3-dihydro-1-benzothien-5-yl)methyl]-5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

To a solution ofN-[(1,1-dioxido-2,3-dihydro-1-benzothien-5-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(102 mg, 0.21 mmol), dichloromethane (1.8 ml) and TFA (0.9 ml) was addedN-iodosuccinimide (47 mg, 0.21 mmol). The mixture was stirred at roomtemperature for 4 h and the solvent was then removed in vacuo. Theresidue was partitioned between EtOAc and aqueous NaHCO₃ and the organicextract was washed with water, dried, filtered and evaporated. The crudeproduct was purified by preparative HPLC to give the title compound as awhite solid (87 mg, 69%).

¹H-NMR (CDCl₃): δ 9.85 (1H, t, J 5.7 Hz); 8.91 (1H, s); 7.83 (1H, d, J8.1 Hz); 7.76 (1H, t, J 8.0 Hz); 7.68 (1H, d, J 8.0 Hz); 7.49 (1H, s);7.41 (2H, d, J 8.0 Hz); 7.34 (1H, s); 4.64 (21H, t, J 6.5 Hz); 3.48 (2H,t, J 6.9 Hz); 3.35 (2H, t, J 7.0 Hz); 2.32 (3H, s).

APCI-MS m/z: 603 [MH⁺].

EXAMPLE 65 5-Iodo-N-f4-{isopropyl(methylsulfonyl)amino]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title product was prepared as described for Example 64 but startingfromN-{4-[isopropyl(methylsulfonyl)-amino]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide.White powder (4 mg, 68%).

¹H-NMR (400 MHz, DMSO-d₆) d 9.77 (1H, t, J=6.1 Hz); 8.61 (1H, s); 7.90(2H, t, J 8.2 Hz); 7.81 (1H, t, J 7.9 Hz); 7.72 (1H, d, J 7.9 Hz); 7.33(2H, d, J 8.2H); 7.21 (2H, d, J 8.3 Hz); 4.51 (2H, d, J 6.0 Hz); 4.30(1H, quintet, J 6.7 Hz); 3.02 (3H, s); 2.20 (3H, s); 1.04 (6H, d, J 6.7Hz).

APCI-MS m/z: 648 [MH⁺].

EXAMPLE 661,2-Dihydro-6-methyl-N-[[4-[(methylsulfonyl)methyl]phenyl-methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamidea)6-Methyl-N-{4-[(methylthio)methyl]benzyl}-2-oxo-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

To a mixture of 13-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylicacid (412 mg, 1.39 mmol), TBTU (527 mg, 1.39 mmol) and DIEA (719 mg,5.56 mmol) in NMP was added [(methylthio)methyl]benzene (232 mg, 1.39mmol) in NMP (1 ml). The reaction was stirred for 1 h at roomtemperature, then diluted with water (15 ml) and extracted with EtOAc.The organic phase was dried (MgSO₄), filtered and evaporated affordingthe crude title compound (620 mg), which was used directly in the nextstep.

b)1,2-Dihydro-6-methyl-N-[[4-[(methylsulfonyl)methyl]phenyl]methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide

To crude6-methyl-N-{4-[(methylthio)methyl]bezyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(620 mg 1.39 mmol) in CH₂Cl₂ (10 ml) cooled to −150° C. was addedm-chloroperoxybenzoic acid (483 mg, 2.8 mmol). The mixture was stirredfor 30 min and then overnight at room temperature. The reaction mixturewas diluted with more CH₂Cl₂ and water, washed with sodium thiosulfate,sodium bicarbonate and brine. The solvent was removed in vacuum and 25mg of the residue was dissolved in CH₃CN/watcr (2.0 ml) and purified ona Xterra@Prep MS C8 column (19×50 mm) using a gradient of CH₃CN/water ata flow rate of 20 ml/min. Freeze drying of the mixture afforded thetitle compound (15 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 9.66 (1H, t, J=5.7 Hz); 9.27 (1H, s); 8.36(1H, d, J 7.4 Hz); 7.86 (2H, d, J 4.5 Hz); 7.78 (1H, t, J 8.0 Hz); 7.68(1H, d, J 7.9 Hz); 7.06 (2H, d, J 8.3 Hz); 6.67 (2H, d, J 85 Hz); 6.60(1H, d, J 7.4 Hz); 433 (2H, d, J 5.8 Hz); 1.99 (3H, s).

APCI-MS m/z: 479.3 [MH⁺].

EXAMPLE 676-Chloro-5-methyl-4-(3-methylphenyl-N-[4-(methylsulfonyl)benzyl]-3-oxo-3,4-dihydropyrazine-2-carboxamidea)6-Chloro-5-methyl-4-(3-methylphenyl)-3-oxo-3,4-dihydropyrazine-2-carbonitrile

The title compound was prepared essentially as described by Gibson. etal. J. Org. Chem. 1994, 59, 1072-1077 and Hoornaert et al. Tetrahedron,1990, 46, 5715-5732.

b)6-Chloro-5-methyl-4-(3-methlphenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylicacid

A solution of6-chloro-5-methyl-4-(3-methylphenyl)-3-oxo-3,4-dihydropyrazine-2-carbonitrile(100 mg, 0.38 mmol) in 11M sulphuric acid (10 ml) was heated at 90° C.for 16 h. Water (200 ml) was added. The water phase was extracted withdichloromethane. The organic layer was dried, filtered and evaporated togive the subtitle compound (20 mg, 19%).

APCI-MS m/z: 279.2 [MH⁺], HPLC Chromolith speedROD RP 18e 504.6 mm, flow2.5 ml/mnin, wavelength 254 nm, time 1.93 nin.

c)6-Chloro-5-methyl-4-(3-methylphenyl-N-[4-(methylsulfonyl)benzyl]-3-oxo-3,4-dihydropyrazine-2-carboxamide

The title compound was prepared starting from6-chloro-5-methyl-4-(3-methylphenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylicacid and (4-methylsulfonyl)benzyl amine as described in Example 17.

¹H-NMR (DMSO-d₆): δ 9.68 (1H, t); 7.87 (2H, d); 7.57 (2H, d); 7.49 (1H,t); 7.36 (1H, d); 7.19 (2H, d); 4.59 (2H, d); 3.18 (3H, s); 2.36 (3H,s); 2.11 (3H, s).

APCI-MS m/z: 446.3 [MH⁺].

EXAMPLE 68 5-Bromo-6-(difluoromethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo1-[3-(trifluoromethyl)pheny-1,2-dihydropyridine-3-carboxamide a) Ethyl6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-1-dihydropyridine-3-carboxylate

The title compound was prepared by stirring a mixture of6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid (20.8 g, 70 mmol) with sodium carbonate (8.16 g, 77 mmol) in NAP(150 ml). Ethyl iodide (15.6 g, 100 mmol) was added slowly (about 10-15minutes) and the mixture stirred at room temperature for 4 h. Water wasadded and the crude product was extracted with EtOAc, washed with waterand dried and filtered. The solvent was removed in vacuo and the residuetriturated with diethyl ether (100 ml), filtered, washed with diethylether and dried to afford the subtitle compound (18 g, 79%) as a whitesolid.

¹H-NMR (CDCl₃): δ 8.21 (1H, d, J 7.4 Hz); 7.75 (1H, d, J 7.9 Hz); 7.68(1H, t, J 7.9 Hz); 7.49 (1H, s); 7.42 (1H, d, J 7.9 Hz); 6.25 (1H, d, J7.4 Hz); 4.36 (2H, q, J 7.2 Hz); 2.03 (3H, s); 1.37 (3H, t, J 7.2 Hz).

APCI-MS m/z: 326 [MH⁺].

b) Ethyl5-bromo-6-(bromomethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate

The subtitle compound (3.25 g, 98%) was prepared by stirring ethyl6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate(2.25 g, 6.9 mmol) with N-bromosuccinimide (2.45 g, 13.8 mmol) andbenzoyl peroxide (35 mg, 0.14 mmol) in carbon tetrachloride (40 ml) at70° C. for 4 h.

¹H-NMR (CDCl₃): δ 8.33 (1H, s); 7.82 (1H, d, J 7.9 Hz); 7.72 (1H, t, J7.9 Hz); 7.62 (1H s); 7.56 (1H, d, J 7.9 Hz); 4.38 (2H, q, J 7.1 Hz);4.164.08 (2H, m); 1.37 (3H, t, J 7.1 Hz).

APCI-MS m/z: 482/484/486 [MH⁺].

c) Ethyl5-bromo-6-(hydroxymethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate

The subtitle compound was prepared in quantitative yield by stirringethyl5-bromo-6-(bromomethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylatewith aqueous sodium bicarbonate in aqueous THF at 60° C. overnight.

¹H-NMR (CDCl₃): δ 8.35 (1H, s); 7.78 (1H, d, J 7.9 Hz); 7.68 (1H, t, J7.9 Hz); 7.57 (1H, s); 7.50 (1H, d, J 7.9 Hz); 4.45-4.33 (4H, m); 137(3H, t, J 7.1 Hz).

APCI-MS m/z: 420/422 [MH⁺].

d) Ethyl5-bromo-6-formyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate

Dimethyl sulphoxide (1.14 g, 1.036 ml, 14.6 mmol) was added dropwise toa solution of oxalyl chloride (0.93 g, 0.64 ml, 7.3 mmol) in dry CH₂Cl₂(40 ml) at −70° C. under an argon atmosphere. After 10 minutes stirring,ethyl5-bromo-6-(hydroxymethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate(2.8 g, 6.66 mmol) in CH₂Cl₂ (10 ml) was added and stirring wascontinued for 20 minutes followed by the addition of triethylamine (3.34g, 4.6 ml, 33 mmol). After a further 15 minutes at low temperature, thereaction mixture was allowed to reach −15° C. and water (20 ml) wasadded. Stirring was continued until the reaction mixture reached roomtemperature. It was then extracted with water and CH₂Cl₂, washed withbrine, dried and filtered. The solvents were removed in vacuo and theresidue purified by column chromatography on silica using CH₂Cl₂ aseluent to afford the title compound (1.46 g, 52%).

¹H-NMR (CDCl₃): δ 9.74 (1H, s); 8.31 (1H, s); 7.75 (1H, d, J 7.9 Hz);7.65 (1H, t, J 7.9 Hz); 7.46 (1H, s); 7.41 (1H, d, J 7.9 Hz); 4.41 (2H,q, J 7.1 Hz); 1.39 (3H, t, J 7.1 Hz).

APCI-MS m/z: 418/420 [MH⁺].

e) Ethyl5-bromo-6-(difluoromethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxylate

The subtitle compound was prepared by stirring ethyl5-bromo-6-fortnyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate(0.98 g, 2.34 mmol) with (diethylamino)sulfur trifluoride (DAST) (378mg, 2.34 mmol) in dry CH₂Cl₂ (20 ml) overnight. Water was added and thereaction mixture was extracted with CH₂Cl₂. The solvents were removed invacuo to afford 1.06 g (100%) of the subtitle compound.

¹H-NMR (CDCl₃): δ 8.29 (1H, brt, J 1.1 Hz); 7.77 (1H, d, J 8.1 Hz); 7.65(1H, t, J 8.1 Hz); 7.53 (1H, s); 7.46 (1H, t, J 8.1 Hz); 6.82 (1H, t, J55.1 Hz); 4.39 (2H, q, J 7.1 Hz); 138 (2H, q, J 7.1 Hz).

APCI-MS m/z: 440/442 [MH⁺].

f)5-Bromo-(difluoromethyl)-N-[4(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was prepared from5-bromo-6-(difluoromethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid (obtained from ethyl5-bromo-6-(difluoromethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylateby alkaline hydrolysis] and 4(methylsulfonyl) benzylamine hydrochlorideusing the method described in Example 17.

¹H NMR (CDCl₃): δ 9.79 (1H, brt, J 5.2 Hz); 8.78 (1H, s); 7.89 (2H, d, J8.4 Hz); 7.82 (1H, d, J 7.8 Hz); 7.70 (1H, t, J 7.8 Hz); 755 (1H, s);7.50 (2H, d, J 8.4 Hz); 7.47 (1H, d, J=7.8 Hz); 6.92 (1H, t, J 51.9H);4.67 (2H, m); 3.02 (3H, s).

APCI-MS m/z: 579/581 [MH⁺].

EXAMPLE 696-(Difluoromethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was prepared by hydrogenation of5-bromo-6-difluoromethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidewith palladium on charcoal (Pd/C) and ammonium formate in methanol.

¹H NMR (CDCl₃): δ 10.00 (1H, brt, J 5.8 Hz); 8.76 (1H, d, J 7.5 Hz);7.89 (2H, d, J 8.2 Hz); 7.87 (1H, d, J 7.9 Hz); 7.77 (1H, t, J 7.9 Hz);7.58 (1H, s); 7.52 (1H, d, J 7.9 Hz); 7.51 (2H, d, J 8.2 Hz); 6.98 (1H,d, J 7.5 Hz); 6.10 (1H, t, J 53.0 Hz); 4.70 (2H, m); 3.03 (3H, s).

APCI-MS m/z: 501 [MH⁺].

The compounds described in Examples 70.1 to 70.50 were prepared by amethod analogous to that described in Examples 1 and 2:

Example 70.1N-(2,3-Dihydro-1,4-benzodioxin-6-ylmethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (DMSO-d₆): δ 9.93 (1H, t); 8.38 (1H, d); 7.88 (2H, d); 7.80 (1H,t); 7.70 (1H, d); 6.79-6.70 (3H, m); 6.62 (1H, d); 4.34 (2H, d); 4.18(4H, s).

APCI-MS m/z: 466.3 [MH⁺].

Example 70.26-Methyl-N-[3-(methylsulfonyl)benzyl]-2-oxo-1-(3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (DMSO-d₆): δ 9.93 (1H, t); 8.38 (1H, d); 7.95-7.45 (8H, m); 6.62(1H, d); 458 (2H, d); 3.18 (3H, s).

Example 70.36-Methyl-N′-[4-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carbohydrazide

¹H NMR (DMSO-d₆): δ 10.80 (1H, s); 9.62 (1H, d); 7.99-7.74 (4H, m); 7.65(2H, d); 6.80 (2H, d); 6.67 (1H, d); 3.07 (3H, s).

Example 70.4N′-(4-Bromophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carbohydrazide

¹HNMR (DMSO-d₆): δ 10.69 (1H, s); 8.35 (1H, d); 7.99-7.73 (4H, m); 7.29(2H, d); 6.66 (3H, dd).

Example 70.5N-[(5-Methoxy-4-oxo-4H-pyran-2-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 435.2 [MH⁺].

Example 70.6N-(4-Cyanobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 412.3 [MH⁺].

Example 70.7N-{[3-(4-Methoxyphenyl)isoxazol-5-yl]methyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 484.4 [MH⁺].

Example 70.8N′-(4-Cyanophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carbohydrazide

APCI-MS m/z: 413.3[MH⁺].

Example 70.96-Methyl-2-oxo-N-[(1-phenyl-1H-pyrazol-4-yl)methyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 467.3 [MH⁺].

Example 70.10N-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)-6-methyl-2-oxo-1-[3(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 445.2 [MH⁺].

Example 70.116-Methyl-N-{[1-(3-methylphenyl-1H-pyrazol-4-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 467.3 [MH⁺].

Example 70.12N′-(4-Chlorophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carbohydrazide

APCI-MS m/z: 422.2 [MH⁺].

Example 70.136-Methyl-2-oxo-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 409.4 [MH⁺].

Example 70.14N-[(1-Ethyl-1H-pyrazol-4-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 405.2 [MH⁺].

Example 70.15N-[(4-Benzylmorpholin-2-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 486.3 [MH⁺].

Example 70.166-Methyl-N-[3-(2-methylpiperidin-1-yl)propyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 436.3 [MH⁺].

Example 70.17 Methyl2-{[({6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-yl}carbonyl)amino]methyl}-3-furoate

APCI-MS m/z: 558.3 [MH⁺].

Example 70.186-Methyl-N-[(1-methyl-1H-pyrazol-1-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 391.2 [MH⁺].

Example 70.19N-(3-Azepan-1-ylpropyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 436.3 [MH⁺].

Example 70.206-Methyl-N-(3-morpholin-4-ylpropyl)-2-oxo-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 424.3 [MH⁺].

Example 70.21 6-Methyl-2-oxo-N-(3-piperidin-1-ylpropyl)-1-[3(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 422.3 [MH⁺].

Example 70.22N-[3-(3,5-Dimethyl-1H-pyrazol-1-yl)propyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 433.3 MH⁺].

Example 70.23N-[3-(2-Ethylpiperidin-1-yl)propyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 450.4 [MH⁺].

Example 70.246-Methyl-N-[2-(1-methyl-1H-imidazol-5-yl)ethyl]-2-oxo-1-[3-trifluoromethyl)phenyl]-1-dihydropyridine-3-carboxamide

APCI-MS m/z: 405.2 [H⁺].

Example 70.25N-[(1-Ethyl-3-methyl-1H-pyrazol-4-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 419.2 [MH⁺].

Example 70.26N-[4-(Acetylamino)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 444.2 [MH⁺].

Example 70.276-Methyl-2-oxo-N-[3-(1H-pyrazol-1-yl)propyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 405.2 [MH⁺].

Example 70.286-Methyl-2-oxo-N-(pyridin-2-ylmethyl)-1-(3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 388.3 [MH⁺].

Example 70.296-Methyl-N-{[1-(4-methylphenyl)-1H-pyrazol-4-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 467.3 [MH⁺].

Example 70.306-Methyl-N′-(4-methylphenyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carbohydrazide

APCI-MS m/z: 402.2 [MH⁺].

Example 70.316-Methyl-N-[3-(4-methylpiperidin-1-yl)propyl]-2-oxo-1-(3-(trifluoromethyl)phenyl-1-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 436.3 [MH⁺].

Example 70.326-Methyl-2-oxo-N-[3-(5-oxo-4,5-dihydro-1H-pyrazol-4-yl)propyl]-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 421.3 [MH⁺].

Example 70.33 Ethyl5-methyl-4-{[({6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-yl}carbonyl)amino]methyl}-2-furoate

APCI-MS m/z: 463.3 [MH⁺].

Example 70.34N-[(6-Fluoro-4H-1,3-benzodioxin-8-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 463.3 [MH⁺].

Example 70.356-Methyl-2-oxo-N-(2-pyridin-3-ylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 402.2 [MH⁺].

Example 70.36N-[(1,3-Dimethyl-1H-pyrazol-4-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 405.2 [MH⁺].

Example 70.376-Methyl-2-oxo-N-(2-pyridin-4-ylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 402.2 [MH⁺].

Example 70.38N′-(4-Fluorophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carbohydrazide

APCI-MS m/z: 406.2 [MH⁺].

Example 70.396-Methyl-N-[(1-methyl-1H-pyrrol-2-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 390.3 [MH⁺].

Example 70.406-Methyl-2-oxo-N′-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carbohydrazide

APCI-MS m/z: 388.3 [MH⁺].

Example 70.41N-[(1-Ethyl-5-methyl-1H-pyrazol-4-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 419.2 [MH⁺].

Example 70.426-Methyl-N-[2-(1-methyl-1H-imidazol-4-yl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 405.2 [MH⁺].

Example 70.43N-[2-(1,3-Dioxolan-2-yl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 397.3 [MH⁺].

Example 70.44N-(1-Benzothien-3-ylmethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 443.3 [MH⁺].

Example 70.45N-[(1,5-Dimethyl-1H-pyrazol-4-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 405.2 [MH⁺].

Example 70.46 N-[2-(3,5-Dimethyl-1H-pyrazol-4-yl)ethyl]-6methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 419.2 [MH⁺].

Example 70.47N-[2-(3,5-Dimethylisoxazol-4-yl)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 420.3 [MH⁺].

Example 70.48N-(3,4-Dihydro-1H-isochromen-1-ylmethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 443.2 [MH⁺].

Example 70.49N-{[(2R)-1-Ethylpyrrolidin-2-yl]methyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 408.3 [MH⁺].

Example 70.506-Methyl-2-oxo-N-[(2R)-tetrahydrofuran-2-ylmethyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 381.2 [MH⁺].

Example 715-Chloro-N-{4-(dimethylamino)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamidea)N-[4-(Benzylthio)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The subtitle compound was prepared as described forN-[4(benzylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide[Example 27 (b)] but excluding the oxidation step. The sub title productwas purified by preparative HPLC (x-terra column, 0.2% ammonia,acetonitrile) to afford the title compound.

¹H NMR (DMSO): δ 9.78 (1H, t, J 6.0 Hz); 8.37 (1H, d, J 7.5 Hz);7.91-7.68 (4H, m); 7.35-7.16 (9H, m); 6.62 (1H, d, J 7.6 Hz); 4.47-4.37(2H, m); 4.20 (2H, s); 2.01 (3H, s).

APCI-MS m/z: 509 [MH⁺].

b)5-Chloro-N-{4-[(dimethylamino)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

ToN-[4-(benzylthio)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(92 mg, 0.18 mmol) was added 50% formic acid/water (18 ml) and CH₂Cl₂ (9ml), The reaction mixture was cooled to −20° C. and chlorine gas wasbubbled through for 1 min. After evaporation of the excess chlorine thereaction mixture was partitioned between CH₂Cl₂ and water. The organicphase was washed with 0.5M aqueous NaHCO₃ and brine, and then dried.After filtration, the solvent was removed in vacuo and the residue wasdissolved in ethanol (10 ml). 5.6M Dimethylamine in ethanol (250 μl) wasadded and the mixture was stirred at room temperature overnight. Afterremoval of the solvent the residue was purified by preparative HPLC(x-terra, 0.2% ammonia, acetonitrile) to afford the title compound (41mg, 43%).

¹H NMR (CDCl₃): δ 9.88-9.81 (1H, m); 8.65 (1H, s); 7.85-7.67 (4H, m);7.51-7.39 (4H, m); 4.73-4.59 (2H, m); 2.68 (6H, s); 2.19 (3H, s).

APCI-MS m/z: 528 [MH⁺].

EXAMPLE 72N-{4-[(Dimethylamino)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide

5-Chloro-N-{4-[(dimethylamino)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(15 mg, 0.028 mmol) was dissolved in hot methanol (1 ml). After coolingto room temperature, ammonium formate (6 mg, 0.1 mmol) and 10% palladiumon carbon (3 mg) were added. The reaction mixture was stirred in asealed vial at room temperature for 4 h. After filtration throughCelite, the solvent was evaporated and the residue was purified bycolumn chromatography on silica using CH₂Cl₂/methanol (98:2) as eluentto afford the title compound (6 mg, 43%).

¹H NMR (CDCl₃): δ 10.01-9.92 (1H, m); 8.59 (1H, d, J 7.5 Hz); 7.85-7.66(4H, m); 7.55-7.41 (4H, m); 6.48 (1H, d, J 7.5 Hz); 4.75-459 (2H, m);2.68 (6H, s); 2.09 (3H, s).

APCI-MS m/z: 494 [MH⁺].

EXAMPLE 735-Chloro-6-methyl-2-oxo-N-[4-(piperazin-1-ylsulfonyl)benzyl]-1-13-(trifluoro-methyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was prepared using the general method of Example 71.

¹H NMR (CDCl₃): δ 9.99-9.82 (2H, m); 8.64 (1H, d, J 8.2 Hz); 7.86-7.62(4H, m); 7.53-1.39 (4H, m); 4.76-4.55 (2H, m); 3.86-2.92 (8H, m); 2.19(3H, s).

APCI-MS m/z: 569 [MH⁺].

Using the general method of Example 72, the compounds of Examples 74 to78 were prepared:

EXAMPLE 746-Methyl-2-oxo-N-[(piperazin-1-ylsulfonyl)benzyl]-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.11-9.79 (2H, m); 8.67-8.50 (1H, m); 7.89-7.38 (8H,m); 6.52-6.43 (1H, m); 4.78-4.52 (2H, m); 3.89-3.62 (2H, m); 3.49-2.94(6H, m); 2.09 (3H, s).

APCI-MS m/z: 535 [MH⁺].

EXAMPLE 756-Methyl-N-[4-(morpholin-4-ylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.05-9.95 (1H, m); 8.58 (1H, d, J 7.5 Hz); 7.84-7.64(4H, m); 7.54-7.41 (4H, m); 6.48 (1H, dd, J 7.4, 0.8 Hz); 4.75-4.59 (2H,m); 3.76-3.69 (4H, m); 3.01-2.94 (4H, m); 2.09 (3H, s).

APCI-MS m/z: 536 [MH⁺].

EXAMPLE 766-Methyl-2-oxo-N-[4-(piperidin-1-ylsulfonyl)benzyl]-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.02-9.92 (1H, m); 8.60 (1H, dd, 7.3 Hz); 7.84-7.64(4H, m); 7.54-7.41 (4H, m); 6.48 (1H, dd, J 7.5, 0.5 Hz); 4.74-4.59 (2H,m); 2.99-2.91 (4H, m); 2.09 (3H, s); 1.68-1.35 (6H, m).

APCI-MS m/z: 534 [MH⁺].

EXAMPLE 776-Methyl-N-{[(methylamino)sulfonyl]benzyl}-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.02-9.92 (1H, m); 8.59 (1H, d, J 7.3 Hz); 7.86-7.70(4H, m); 7.54-7.41 (4H, m); 6.48 (1H, d, J 73H); 4.73-4.58 (E, m); 4.29(1H, s); 2.63 (3H, s); 2.09 (3H, s).

APCI-MS m/z: 480 [MH⁺].

EXAMPLE 786-Methyl-2-oxo-N-[4-(pyrrolidin-1-ylsulfonyl)benzyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.00-991 (1H, m); 8.60 (1H, d, J 7.5H); 7.85-7.68(4H, m); 7.53-7.40 (4H, m); 6.48 (1H, dd, J 7.5, 0.7 Hz); 4.76-4.58 (2H,m); 3.26-3.16 (4H, m); 2.09 (3H, s); 1.80-1.70 (4H, m).

APCI-MS m/z: 520 [MH⁺].

EXAMPLE 795-Chloro-6-methyl-2-oxo-N-[4-(pyrrolidin-1-ylsulfonyl)benzyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was prepared using the general method of Example 71.

¹H NMR (CDCl₃): δ 9.89-9.79 (1H, m); 8.66 (1H, s); 7.86-7.72 (4H, m);7.52-7.40 (4H, m); 4.74-4.59 (2H, m); 3.25-3.17 (4H, m); 2.19 (3H, s);1.78-1.72 (4H, m).

APCI-MS m/z: 554 [MH⁺].

EXAMPLE 805-Chloro-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide

6-Methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide[Example 1.1] (50 mg, 0.108 mmol) was dissolved in acetonitrile (1 ml)and cooled to 0° C. KNO₃ (16 mg, 0.16 mmol) and sulfuryl chloride (13μl, 0.16 mmol) were added. The reaction mixture was stirred for 1 h at0° C., followed by the addition of saturated aqueous Na₂CO₃ and diethylether. The aqueous phase was extracted with diethyl ether and thecombined organic phase was washed with brine and dried. Afterfiltration, the solvent was removed in vacuo, the residue was dissolvedin methanol, a white precipitate appeared and was filtered off and driedto afford the title compound (22 mg, 41%).

¹H NMR (CDCl₃): δ 9.93-9.80 (1H, m); 8.64 (1H, s); 7.94-7.69 (4H, m);7.57-7.37 (4H, m); 4.75-4.57 (2H, m); 3.01 (3H, s); 219 (3H, s).

APCI-MS m/z: 499 [MH⁺].

EXAMPLE 81N-{4-[(Acetylamino)sulfonyl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide

N-[4-(Aminosulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide[Example 1.5] (16 mg, 0.034 mmol) was dissolved in CH₂Cl₂ (1 ml).Powdered KOH (6 mg, 0.11 mmol) and 10% acetyl chloride in CH₂Cl₂ (25 μl,0.035 mmol) were added and the mixture was stirred at room temperaturefor 1.5 h. Water and 1M aqueous HCl were added. The reaction mixture wasextracted with CH₂Cl₂. The organic phase was washed with water, brineand dried. The solvent was removed in vacuo and the residue was purifiedby preparative HPLC (x-terra, 0.2% ammonia, acetontrile) to afford thetitle compound (7 mg, 41%).

¹H NMR (CDCl₃): δ 10.03-9.96 (1H, m); 8.58 (1H, d, J 7.4 Hz); 8.16 (1H,s); 7.98-7.93 (2H, m); 7.83-7.71 (2H, m); 7.53-7.42 (4H, m); 6.47 (1H,d, J 7.4 Hz); 4.72-4.59 (2H, m); 2.08 (3H, s); 2.02 (3H, s).

APCI-MS m/z: 508 [MH⁺].

Using the general method of Example 10, the compounds of Examples 82 and83 were prepared.

EXAMPLE 82N-[4-(Isopropylsulfonyl)benzyl]-5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.90 (1H, t, J=5.7 Hz); 8.91 (1H, s); 7.83-7.80 (3H,m); 7.76 (1H, t, J=7.9 Hz); 7.50-7.48 (3H, m); 7.41 (1H, d, J 7.8 Hz);4.68 (2H, t, 36.2 Hz); 3.15 (1H, m); 2.31 (3H, s); 1.28 (6H, d, 36.89Hz).

APCI-MS m/z: 619 [MH⁺].

EXAMPLE 83N-[4-(Cyclopropylsulfonyl)benzyl]-5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.86 (1H, t, J 5.8 Hz); 8.90 (1H, s); 7.83-7.80 (3H,m); 7.75 (1H, t, J=7.8 Hz); 7.49-7.47 (3H, m); 7.40 (1H, d, J 7.8 Hz);4.66 (2H, t, J 5.7 Hz); 2.42 (1H, m); 2.31 (3H, s); 1.32 (2H, m); 1.01(2H, m).

APCI-MS m/z: 617 [MH⁺].

EXAMPLE 841,2-Dihydro-6-methyl-N-[[4-[(methylsulfonyl)oxy]phenyl]methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide

The title compound (31 mg, 46%) was prepared fromN-4-hydroxybenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamideand benzensulfonyl chloride using the general method of Example 61.

¹H NMR (DMSO-d₆) δ 9.87 (1H, t, J=6.0 Hz); 8.38 (1H, d, J 7.5 Hz); 7.89(2H, d, J 8.9 Hz); 7.80 (1H, t, J=7.8 Hz); 7.72 (1H, d, J 7.9 Hz); 7.39(2H, d, J 8.6 Hz); 7.29 (2H, d, J 8.6 Hz); 6.62 (1H, d, J 7.5 Hz); 4.50(2H, d, J 6.0 Hz); 3.35 (3H, s); 2.02 (3H, s).

APCI-MS m/z: 543.3 [MH⁺].

EXAMPLE 85N-[4-(1,1-Dioxidoisothiazolidin-2-yl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound (12 mg, 9.5%) was prepared fromN-(4-aminobenzyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroproline-3-4-carboxamideand 3-chloropropanesulfonyl chloride using the general method of Example56.

¹H NMR (DMSO-d₆) δ 9.78 (1H, t, J 5.8 Hz); 8.37 (1H, d, f 7.4 Hz); 7.88(2H, d, J 7.6 Hz); 7.79 (1H, t, J=7.8 Hz); 7.70 (1H, d, J 8.2 Hz); 7.28(2H, d, 38.6 Hz); 7.14 (2H, d, J 8.5 Hz); 6.61 (1H, d, J 7.5 Hz); 4.43(2H, d, J 5.8 Hz); 3.69 (2H, t, J 6.5 Hz); 3.47 (2H, t, J 7.4 Hz); 2.38(2H, quintet, J 7.0 Hz); 2.01 (3H, s).

APCI-MS m/z 506.3 [MH⁺].

EXAMPLE 86 6-Methyl-2oxo-N-[[4-(4-pyridinylsulfonyl)phenyl]methyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidea) 1-[4(Pyridin-4-ylsulfonyl)phenyl]methanamine

To a mixture of 4-mercaptopyridine (0.8 g, 7.2 mmol) and K₂CO₃ (2.0 g,14.4 mmol) in NMP, 4-fluorobenzaldehyde (0.99 g, 8.0 mmol) was added.The mixture was then stirred at 70° C. for 3 h. After cooling, thereaction mixture was diluted with water (5.0 ml) and extracted withEtOAc. The organic solvent was evaporated and the residue dissolved inmethanol. Sodium borohydride (0.57 g, 15 mmol) was added and the mixturestirred for 3 h at room temperature. After addition of water, themethanol was removed in vacuo and the residue extracted with CH₂Cl₂. Theorganic phase was dried over MgSO₄, filtered, and evaporated and theresidue was dissolved in toluene (10 ml). The toluene solution washeated to 40° C., phosphorus tribromide (0.25 g, 0.92 mmol) was addedand the temperature increased to 100° C. for 30 minutes. After cooling,water (50 ml) was added and the mixture extracted with EtOAc. Theorganic phase was evaporated, the residue dissolved in methanol andslowly added to a mixture of 25% ammonia (15 ml) in methanol (10 ml).After stirring for 3 h at room temperature the subtitle compound wasobtained. (0.30 g, 37% b) as a white solid

APCI-MS m/z: 217.2 [MH⁺].

b)6-Methyl-2-oxo-N-[[4(4-pyridinylsulfonyl)phenyl]methyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

To a mixture of6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid (0.28 g, 0.92 mmol), HBTU (0.35 g, 0.92 mmol) and DIEA (0.24 g,1.84 mmol) in NMP was added1-[4-(pyridin-4-ylsulfonyl)phenyl]methanamine (0.20 g, 0.92 mmol) in NW(1 ml). The reaction mixture was stirred for 1 h at room temperature,then diluted with water (15 ml) and extracted with EtOAc. The organicphase was dried (MgSO₄), filtered and evaporated. To the residuedissolved in CH₂Cl₂ (10 ml) cooled to −15° C. was addedm-chloroperoxybenzoic acid (0.48 g, 2.76 mmol). The mixture was stirredfor 30 min and then overnight at room temperature. The reaction mixturewas diluted with more CH₂Cl₂ and water, washed with Na₂S₂O₃, NaHCO₃ andbrine. The solvent was removed in vacuo and 25 mg of the residue wasdissolved in acetonitrile/water (2.0 ml) and purified on a Xterra@PrepMS C8 column (19×50 mm) using a gradient of acetonitrile/water at a flowrate of 20 ml/min. Freeze drying of the mixture afforded the tidecompound (12 mg, 49%).

¹H NMR (DMSO-d₆) δ 9.92 (1 H, t, J 6.0 Hz); 8.85 (2H, dd, J 4.4, 1.6Hz); 8.34 (1H, d, J 7.5 Hz); 7.96 (2H, dd, J 6.7, 1.7 Hz); 7.90 (4H, m);7.87 (1H, t, J 4.4, 1.6 Hz); 7.71 (1H, d, J 79 Hz); 7.54 (2H, d, J 8.4Hz); 6.61 (2H, d, J 8.2 Hz); 4.55 (2H, d, J 6.0 Hz); 2.01 (3H, s).

APCI-MS m/z: 528.4 [MH ⁺].

Starting from6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid and the appropriate methanamine denzvative and using the generalmethod of Example 86, the compounds of Examples 87 to 91, 92(b) and93(b) were prepared:

EXAMPLE 876-Methyl-2-oxo-N-[4-(phenylsulfonyl)benzyl]-1-3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound (34 mg, 21%) was prepared using1-[4-(phenylthio)phenyl]methanamine (from thiophenol and4-fluorobenzaldehyde).

¹H NMR (CDCl₃) δ 9.90 (1H, t, J 6.0 Hz); 8.34 (1H, d, J 7.5 Hz); 7.90(6H, m); 7.80 (1H, t, J 8.1 Hz); 7.78 (2H, m); 7.59 (2H, t, J 7.5 Hz);7.49 (2H, d, J 8.4 Hz); 6.60 (1H, d, J 7.7 Hz); 4.53 (2H, d, J 6.2 Hz);2.01 (3H, s).

APCI-MS m/z: 527.4 [MH⁺].

EXAMPLE 886-Methyl-2-oxo-N-[4-(1,3-thiazol-2-ylsulfonyl)benzyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound (50 mg, 21%) was prepared using1-[4-(1,3-thiazol-2-ylsulfonyl)phenyl]methanamine (from2-mercaptothiazole and 4-fluorobenzaldehyde).

¹H NMR (400 MHz, DMSO-d₆) δ 9.91 (1H, t, 6.1 Hz); 8.32 (1H, d, J 11.8Hz); 8.23 (1H, d, 37.9 Hz); 8.06 (1H, d, 33.1 Hz); 7.95 (2H, d, 38.4Hz); 7.87 (2H, d, J 7.2 Hz); 7.78 (1H, t, J=7.9 Hz); 7.68 (1H, t, J=75Hz); 7.54 (2H, d, J 8.4 Hz); 6.59 (1H, d, J 7.7 Hz); 4.54 (2H, d, J 6.4Hz); 1.99 (3H, s).

APCI-MS m/z: 534.3 [MH⁺].

EXAMPLE 896-Methyl-2-oxo-N-(pyridmidin-2-ylsulfonyl)benzyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound (10 mg, 23%) was prepared using1-[4-(pyrimidin-2-ylsulfonyl)phenyl]methanamine (from2-mercaptopyrimidine and 4-fluorobenzaldehyde).

¹H NMR (DMSO-d₆): δ 9.63 (1H, t, J 6.1 Hz); 8.69 (1H, d, J 4.9 Hz); 8.05(1H, d, J 7.5 Hz); 7.60 (4H, q, J 8.6 Hz); 7.45 (3H, m); 7.23 (2H, d, J83 Hz); 6.30 (1H, d, J 7.4 Hz); 4.27 (2H, d, J 6.6 Hz); 1.70 (3H, s).

APCI-MS m/z: 529.3 [MH⁺].

EXAMPLE 90N-[4-(1H-Imidazol-2-ylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound (8 mg, 16%) was prepared using 1-[4(1H-imidazol-2-ylsulfonyl)phenyl]methanamine (from 2-mercaptoimidazoleand 4-fluorobenzaldehyde).

¹H NMR (DMSO-d₆) δ 9.91 (1H, t, J=6.2 Hz); 8.35 (2H, d, J 7.4 Hz); 7.88(4H, t, J 8.4 Hz); 7.80 (1H, t, J 7.7 Hz); 7.72 (1H, d, J 7.9 Hz); 7.52(2H, d, J 8.3 Hz); 7.27 (1H, s); 6.61 (1H d, J 7.5 Hz); 5.75 (1H, s);4.54 (2H, d, J 6.0 Hz); 2.02 (3H, s).

APCI-MS m/z: 517.3 [MH⁺].

EXAMPLE 916-Methyl-N-{4-[(1-methyl-1H-1,2,4-triazol-5-yl)sulfonyl]benzyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound (6 mg, 15%) was prepared using1-{4-[(1-methyl-1H-1,2,4-triazol-5-yl)sulfonyl]phenyl}methanamine (from3-mercapto-4-methyl-4H-1,2,4-triazole and 4-fluorobenzaldehyde).

¹H NMR (DMSO-d₆) δ 9.95 (1H, t, J 6.0 Hz); 8.74 (1H, s); 8.36 (1H, d, J7.5 Hz); 7.99 (2H, d, J 8.4 Hz); 7.89 (2H, d, J 8.5 Hz); 7.80 (2H, t, J7.8 Hz); 7.72 (1H, d, J 7.8 Hz); 7.59 (2H, d, J 8.4 Hz); 6.62 (1H, d, J7.3 Hz); 4.59 (2H, d, J 6.3 Hz); 3.86 (3H, s); 2.02 (3H, s).

APCI-MS m/z: 532.3 [MH⁺].

EXAMPLE 926-Methyl-N-{4[(5-methyl-1,3-oxazol-4-yl)sulfonyl]benzyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidea) 1-{4-[(5-Methyl-1,3-oxazol-4-yl)sulfonyl]phenyl}methanamine

To 5-methyl-4-[(4-methylphenyl)sulfonyl]-1,3-oxazole (prepared accordingto J. Chem. Soc., Perkin Trans. 1, 2000, 527-531) (3.7 g, 15.6 mmol)dissolved in chlorobenzene, N-bromosuccinimide (3.5 g, 19.6 mmol) and2,2′-azobis(2-methylpropinitrile) (0.27 g, 1.6 minor) were added. Thereaction mixture was then stirred and heated to 60° C. Bromine (0.104 g,0.65 mmol) was added and the mixture heated to 90° C. for an additional2 h. to After cooling, 2% aqueous NaHSO₃ (10 ml) and water (40 ml) wereadded and the mixture extracted with EtOAc. The organic phase wasevaporated, the residue dissolved in methanol and slowly added to amixture of 25% ammonia (150 ml) in methanol (100 ml). After stirring for3 h at room temperature the ammonia was removed in vacuo and the waterphase extracted with EtOAc. The organic phase was dried (MgSO₄),filtered and is evaporated affording the subtitle compound (2 g, 51%).

b)6-Methyl-N-{4-[(5-methyl-1,3-oxazolyl)sulfonyl]benzyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound (7 mg, 21%) was prepared using1-{4-[(5-methyl-1,3-oxazol-4-yl)sulfonyl]phenyl}methanamine.

¹H NMR (MSO-d₆) δ 9.92 (1H, t, J 6.0 Hz); 8.39 (1H, s); 8.35 (1H, d, J7.4 Hz); 7.88 (4H, t, J 5.4 Hz); 7.80 (1H, t, J 8.2 Hz); 7.71 (1H, d,38.2 Hz); 7.52 (2H, d, J 8.1 Hz); 6.61 (1H, d, J 7.5 Hz); 4.55 (2H, d,36.1 Hz); 2.64 (3H, s); 2.02 (3H, s); 1.91 (2H, s).

APCI-MS m/z: 532.3 [MH⁺].

EXAMPLE 936-Methyl-N-{[6-(methylsulfonyl)pyridin-3-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidea) 1-[6-(Methylsulfonyl)pyridin-3-yl]methanamine

To 2-chloropyridine-5-carboxyaldehyde (0.50 g, 3.5 mmol) in THF (5 ml),sodium methanethiolate (0.50 g, 7.0 mmol) was added. The mixture wasthen stirred at 70° C. overnight. After cooling, the reaction mixturewas diluted with water (15 ml) and extracted with EtOAc. The organicphase was evaporated and the residue dissolved in methanol. Sodiumborohydride (0.26 g, 7.0 mmol) was added and the mixture stirred for 3 hat room temperature. After addition of water, the methanol was removedin vacuo and the residue extracted with CH₂Cl₂. The organic phase wasdried (MgSO₄), filtered, evaporated and treated with CH₂Cl2 (50 ml). Tothe CH₂Cl₂ mixture, phosphorus tribromide (0.25 g, 0.92 mmol) was addedand the mixture stirred overnight at room temperature. Water (50 ml) wasthen added and the mixture extracted with EtOAc. Finally, the organicphase was evaporated, the residue dissolved in methanol and slowly addedto a mixture of 25% ammonia (20 ml) in methanol (20 ml). After stirringfor 3 h at room temperature the subtitle compound was obtained.

b)6-Methyl-N-{[6-(methylsulfonyl)pyridin-3-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound (12 mg, 24%) was prepared using[6-(methylsulfonyl)pyridin-3-yl]methylamine1-[6-(methylsulfonyl)pyridin-3-yl]methanamine.

¹H-NMR (DMSO-d₆) δ 9.98 (1H, t, J 6.1 Hz); 8.71 (1H, s); 8.36 (1 d, J7.5 Hz); 8.01 (2H, s); 7.90 (2H, d, J 8.3 Hz); 7.81 (1H, t, J 7.7 Hz);7.72 (1H, d, J 7.9 Hz); 6.62 (1H, d, J 7.5 Hz); 4.61 (2H, d, 36.1 Hz);3.25 (3H, s); 2.03 (3H, s).

APCI-MS m/z: 466.3 [MH³⁰].

EXAMPLE 945-Fluoro-6-methyl-N-[4-(methylsulfonyl)benzyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

To6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide[Example 1.1] (0.25 g, 0.54 mmol) in acetonitrile (4.5 ml) under argon,1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate)(0.45 g, 1.27 mmol) was added. The reaction mixture was heated at 80° C.for 2 h. Water was then added and the product purified on a Xterra@PrepMS C8 column (19×50 mm) using a gradient of acetonitrile/water at a flowrate of 20 ml/min. Freeze drying of the mixture afforded the titlecompound (75 mg, 29%).

¹H NMR (CDCl₃) δ 10.02 (1H, t, J 5.4 Hz); 8.57 (1H, d, J 9.0 Hz); 7.88(2H, d, J 8.4 Hz); 7.84 (1H, d, J 8.1 Hz); 7.76 (1H, t, J 7.9 Hz); 7.51(4H, d, J 8.4 Hz); 7.44 (1H, d, J 8.0 Hz); 4.67 (2H, t, J 5.7 Hz); 3.05(3H, s); 2.08 (3H, d, J 3.3 Hz).

APCI-MS m/z: 483.3 [MH⁺].

EXAMPLE 95N-[4-(methylsulfonyl)benzyl]-2-oxo-6-(2-oxoethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

Phosphorus oxychloride (1.8 ml, 19.7 mmol) was added dropwise underargon to a stirred ice-cooled solution of dry N,N-dimethylformamide (2.8ml). After the addition, the cooling was stopped and the mixture wasstirred at room temperature for 30 min. Dry dichloromethane (10 ml) wasadded and the solution was cooled to −20° C. 6-Methyl-N-[4(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (1.1 g, 2.4 mmol) was added insmall portions at such a rate that the temperature did not rise above 1°C. After 15 min. at 0° C., potassium carbonate (3.4 g, 24.6 mmol) wasadded and the mixture was heated to reflux for 20 min. The reactionmixture was cooled and poured into a cooled solution of 50% aqueoussodium carbonate (200 ml) and stirred at room temperature for 5 h. Themixture was extracted with ethyl acetate. The organic layers were washedwith water, brine, dried, filtered and concentrated at reduced pressureto give a dark oil. A part of the oil was purified by preparative HPLCto give the title compound as a yellow solid.

¹H NMR (CDCl₃): δ 10.06 (1H, t, J 5.3H); 9.47 (1H, s); 8.66 (1H, d, 37.4Hz); 7.89 (2H, d, J 8.2 Hz); 7.82 (1H, d, J 8.1 Hz); 7.71 (1H, t, J 7.9Hz); 7.53-7.49 (3H, m); 7.41 (1H, d, J 8.2 Hz); 6.50 (1H, d, J 7.4 Hz);4.69 (2H, t, J 5.6 Hz); 3.60 (2H, s); 3.02 (3H, s).

APCI-MS m/z: 493 [MH⁺].

EXAMPLE 965-Ethyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

A mixture of6-methyl-N-(4-(methylsulfonyl)benzyl]-2-oxo-1-(3-(trifluoromethyl)phenyl]-5-vinyl-1,2-dihydropyridine-3-carboxamide (patent application SE03024874) (58 mg, 0.12 mmol), 5% palladium on carbon (11 mg) in ethanol(15 ml) and EtOAc (15 ml) was stirred vigorously under a hydrogenatmosphere for 16 h. The mixture was filtered through Celite, thefiltrate was evaporated to dryness and the residue was purified bypreparative HPLC to give the title compound as a white solid (33 mg,56%).

¹H-NMR (CDCl₃): δ 10.09 (1H, t, J=5.7 Hz); 8.55 (1H, s); 7.87 (2H, d, J8.3 Hz); 7.80 (1H, d, J 7.8 Hz); 7.74 (1H, t, f 7.9 Hz); 7.52 (2H, d, J8.4 Hz); 7.50 (1H, s); 7.43 (1H, d, J 7.6 Hz); 4.67 (2H, t, J 6.4 Hz);3.01 (3H, s); 2.59 (2H, q, J 7.5 Hz); 2.04 (3H, s); 1.23 (3H, t, J=7.5Hz).

APCI-MS m/z: 493 [MH⁺].

Screen

Human Neutrophil Elastase Quenched-FRET Assay

The assay uses Human Neutrophil Elastase (HNE) purified from serum(Calbiochem art. 324681; Ref. Baugh, R J. et al., 1976, Biochemistry.15, 836-841). HNB was stored in 50 mM NaOAc, 200 mM NaCl, pH 5.5 withadded 30% glycerol at −20° C. The protease substrate used was ElastaseSubstrate V Fluorogenic, MeOSuc-AAPV-AMC (Calbiochem art. 324740; Ref.Castillo, M. J. et al., 1979, Anal. Biochem. 99, 53-64). The substratewas stored in DMSO at −20° C. The assay additions were as follows: Testcompounds and controls were added to black 96-well flat-bottom plates(Greiner 655076), 1 μL in 100% DMSO, followed by 30 μL HNE in assaybuffer with 0.01% TritonX-100. The assay buffer constitution was: 100 mMTris (pH 7.5) and 500 mM NaCl. The enzyme and the compounds wereincubated at room temperature for 15 minutes. Then 30 μl substrate inassay buffer was added The assay was stopped after 30 minutes incubationat room temperature by adding 60 μl stop solution (140 mM acetic acid,200 mM sodium monochloroacetate, 60 mM sodium acetate, pH 4.3).Fluorescence was measured on a Wallac 1420 Victor 2 instrument atsettings: Exitation 380 nm, Emission 460 nm. IC₅₀ values were determinedusing xlfit curve fitting using model 205.

When tested in the above screen, the compounds of the Examples gave IC₅₀values for inhibition of human neutrophil elastase activity of less than30 μM, indicating that the compounds of the invention arm expected topossess useful therapeutic properties. Specimen results are shown in thefollowing Table: Inhibition of Human Neutrophil Elastase Compound IC₅₀(nM) 1-(3-Bromophenyl)-N-(4-methoxybenzyl)-6-methyl- 3532-oxo-1,2-dihydropyridine-3-carboxamide6-Methyl-N-[(5-methylisoxazol-3-yl)methyl]- 3182-oxo-1-[3-(trifluoromethyl)phenyl]-1,2- dihydropyridine-3-carboxamideN-(2,3-Dimethoxybenzyl)-6-methyl-2-oxo-1- 701[3-(trifluoromethyl)phenyl]-1,2- dihydropyridine-3-carboxamideN-(2,3-Dihydro-1-benzofuran-5-ylmethyl)- 20252,4-dioxo-3-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

1. A compound of formula (I)

wherein: X represents O or S; Y¹ represents N or CR²; and when R¹represents OH, Y¹ may also, in the tautomeric form, represent NR⁶; Y²represents CR³; and when Y¹ represents CR², then Y² may also representN; R¹ represents H or C1 to 6 alkyl; said alkyl being optionallysubstituted by one or more substituents selected independently fromhalogen, CN, CHO, OR⁷, NR⁸R⁹, S(O)_(m)R¹⁰ and SO₂NR¹¹R¹²; and, when Yrepresents N, R¹ may also represent OH; R⁷ represents H, C1 to 6 alkylor phenyl; said phenyl being optionally further substituted by halogen,C1 to 6 alkyl and C1 to 6 alkoxy, R² represents H, halogen or C1 to 6alkyl; R³ represents H or F; G¹ represents phenyl or a five- orsix-membered heteroaromatic ring containing 1 to 3 heteroatomsindependently selected from O, S and N; or G¹ represents a five- orsix-membered saturated or partially unsaturated cycloalkyl ring; or G¹represents a five- or six-membered saturated or partially unsaturatedheterocyclic ring containing one heteroatom selected from O, S and NR¹³where R¹³ represents H or C1 to 6 alkyl; R⁵ represents H, halogen, C1 to6 alkyl, CN, C1 to 6 alkoxy, NO₂, NR¹⁴R¹⁵, C1 to 3 alkyl substituted byone or more F atoms or C1 to 3 alkoxy substituted by one or more Fatoms; R¹⁴ and R¹⁵ independently represent H or C1 to 3 alkyl; saidalkyl being optionally further substituted by one or more F atoms; nrepresents an integer 1, 2 or 3 and when n represents 2 or 3, each R⁵group is selected independently; R⁴ and R⁶ independently represent H orC1 to 6 alkyl; said alkyl being optionally further substituted by OH orC1 to 6 alkoxy; or R⁴ and L are joined together such that the group—NR⁴L represents a 5 to 7 membered azacyclic ring optionallyincorporating one further heteroatom selected from O, S and NR¹⁶; Lrepresents a bond, O, NR²⁹ or C1 to 6 alkyl; said alkyl optionallyincorporating a heteroatom selected from O, S and NR¹⁶; and said alkylbeing optionally further substituted by OH or OMe; G² represents amonocyclic ring system selected from: i) phenyl or phenoxy, ii) a 5 or 6membered heteroaromatic ring containing one to three heteroatomsindependently selected from O, S and N, iii) a C3 to 6 saturated orpartially unsaturated cycloalkyl, or iv) a C4 to 7 saturated orpartially unsaturated heterocyclic ring containing one or twoheteroatoms independently selected from O, S(O)_(p) and NR¹⁷ andoptionally further incorporating a carbonyl group; or G² represents abicyclic ring system in which each of the two rings is independentlyselected from: i) phenyl, ii) a 5 or 6 membered heteroaromatic ringcontaining one to three heteroatoms independently selected from O, S andN, iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or iv)a C4 to 7 saturated or partially unsaturated heterocyclic ringcontaining one or two heteroatoms independently selected from O,S(O)_(p) and NR¹⁷ and optionally further incorporating a carbonyl group;and the two rings are either fused together, or are bonded directlytogether or are separated by a linker group selected from O, S(O)_(q) orCH₂, said monocyclic or bicyclic ring system being optionally furthersubstituted by one to three substituents independently selected from CN,OH, C1 to 6 alkyl, C1 to 6 alkoxy, halogen, NR¹⁸R¹⁹, NO₂, OSO₂R³⁸,CO₂R²⁰, C(═NH)NH₂, C(O)NR²¹R²², C(S)NR²³R²⁴, SC(═NH)NH₂, NR³¹C(═NH)NH₂,S(O)_(s)R²⁵, SO₂NR²⁶R²⁷, C1 to 3 alkoxy substituted by one or more Patoms and C1 to 3 alkyl substituted by SO₂R³⁹ or by one or more F atoms;or when L does not represent a bond, G may also represent H; m, p, q, sand t independently represent an integer 0, 1 or 2; R⁸ and R⁹independently represent H, C1 to 6 alkyl, formyl or C2 to 6 alkanoyl;said alkyl being optionally further substituted by phenyl optionallysubstituted by halogen, C1 to 6 alkyl, C1 to 6 alkoxy or SO₂R³⁰; or thegroup NR⁸R⁹ together represents a 5 to 7 membered azacyclic ringoptionally incorporating one further heteroatom selected from O, S andNR²⁸; R¹⁸ and R¹⁹ independently represent H, C1 to 6 alkyl, formyl, C2to 6 alkanoyl, S(O)_(t)R³² or SO₂NR³³R³⁴; said alkyl group beingoptionally further substituted by halogen, CN, C1 to 4 alkoxy orCONR⁴¹R⁴²; R²⁵ represents H, C1 to 6 alkyl or C3 to 6 cycloalkyl; saidalkyl group being optionally further substituted by one or moresubstituents selected independently from OH, CN, CONR³⁵R³⁶, CO₂R³⁷,OCOR⁴⁰, C3 to 6 cycloalkyl, a C4 to 7 saturated heterocyclic ringcontaining one or two heteroatoms independently selected from O,S(O)_(p) and NR⁴³ and phenyl or a 5 or 6 membered heteroaromatic ringcontaining one to three heteroatoms independently selected from O, S andN; said aromatic ring being optionally further substituted by one ormore substituents selected independently from halogen, CN, C1 to 4alkyl, C1 to 4 alkoxy, OH, CONR⁴⁴R⁴⁵, CO₂R⁴⁶, S(O)_(s)R⁴⁷ and NHCOCH₃;R²⁶ and R²⁷ independently represent H, C1 to 6 alkyl, formyl or C2 to 6alkanoyl; R³² represents H, C1 to 6 alkyl or C3 to 6 cycloalkyl; R³⁸represents H, C1 to 6 alkyl or phenyl; said phenyl being optionallyfurther substituted by halogen, C1 to 6 alkyl or C1 to 6 alkoxy; R¹⁰,R¹¹, R¹², R¹⁶, R¹⁷, R²⁰, R²¹, R²², R²³, R²⁴, R²⁸, R²⁹, R³⁰, R³¹, R³³,R³⁴, R³⁵, R³⁶, R³⁷, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶ and 47independently represent H or C1 to 6 alkyl; and pharmaceuticallyacceptable salts thereof, with the proviso that the following compoundsare disclaimed:N-benzyl-5,6-dimethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide;N-(2-phenethyl)-5,6-dimethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide;N-(2-hydroxyethyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide;N-[2-(dimethylamino)ethyl)-2,dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide;4-[2-[[1,2-dihydro-1-(4-methylcyclohexyl)-2-oxo-3-pyridinyl]carbonyl]amino]ethyl]benzoicacid; and4-[2-[[(1-cyclohexyl-1,2-dihydro-2-oxo-3-pyridinyl]carbonyl]amino]ethyl]-benzoicacid.
 2. A compound according to claim 1 wherein X represents
 0. 3. Acompound according to claim 1 or claim 2 wherein R² and R³ eachrepresent H.
 4. A compound of formula (I), according to any one ofclaims 1 to 3, wherein G¹ represents phenyl or pyridyl.
 5. A compound offormula (I), according to claim 1, or a pharmaceutically acceptable saltthereof, for use as a medicament.
 6. A pharmaceutical formulationcomprising a compound of formula (I), as defined in any one of claims 1to 4, or a pharmaceutically acceptable salt thereof, optionally inadmixture with a pharmaceutically acceptable diluent or carrier.
 7. Amethod of treating, or reducing the risk of, a human disease orcondition in which inhibition of neutrophil elastase activity isbeneficial which comprises administering to a person suffering from orsusceptible to such a disease or condition, a therapeutically effectiveamount of a compound of formula (I), as defined in any one of claims 1to 4, or a pharmaceutically acceptable salt thereof.
 8. The use of acompound of formula (I) as defined in any one of claims 1 to 4, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment or prophylaxis of human diseases orconditions in which inhibition of neutrophil elastase activity isbeneficial.
 9. The use of a compound of formula (I) as defined in anyone of claims 1 to 4, or a pharmaceutically acceptable salt thereof, inthe manufacture of a medicament for the treatment or prophylaxis ofinflammatory diseases or conditions.
 10. A process for the preparationof a compound of formula (I), as defined in any one of claims 1 to 4,and optical isomers, racemates and tautomers thereof andpharmaceutically acceptable salts thereof, which comprises: reacting acompound of formula (II)

wherein R¹, R⁵, Y¹, Y², X, G¹ and n are as defined in claim 1 and L¹represents a leaving group, with an amine of formula (III) or a saltthereof

wherein R⁴, G² and L are as defined in claim 1, and where desired ornecessary converting the resultant compound of formula (I), or anothersalt thereof, into a pharmaceutically acceptable salt thereof; orconverting one compound of formula (I) into another compound of formula(I); and where desired converting the resultant compound of formula (I)into an optical isomer thereof.